Abuse deterrent formulations of amphetamine

ABSTRACT

The present invention relates generally to abuse-deterrent formulations containing dextroamphetamine sulfate.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/943,131, filed Apr. 2, 2018 and issued as U.S. Pat. No. 10,471,015,which is a continuation of U.S. patent application Ser. No. 15/591,677,filed May 10, 2017 and issued as U.S. Pat. No. 9,931,303, which claimspriority to, and benefit of, the U.S. Provisional Application No.62/455,227, filed Feb. 6, 2017, the contents of each of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to abuse deterrent oralformulations.

BACKGROUND OF THE INVENTION

The design and development of an abuse deterrent formulation involvesthe balance of limiting the potential for manipulation and abuse whilemaintaining acceptable dissolution rates and bioavailability. At thesame time, the formulation must have processing characteristics thatenables commercial manufacturing of dosage units. Because of thesechallenges, there is a need for a suitable abuse deterrent formulation.

SUMMARY OF THE INVENTION

The application provides an abuse-deterrent formulation having amedicament; and at least two excipients. The medicament, is typically acontrolled substance. The controlled substance may target the centralnervous system and/or may be used to treat psychiatric disorders. Apreferred medicament is an amphetamine such as dextroamphetamine, or apharmaceutically acceptable salt thereof.

In specific embodiments, the medicament has a formula

or a pharmaceutically acceptable salt thereof. In further specificembodiments, the medicament is the S enantiomer, or a pharmaceuticallyacceptable salt thereof.

Excipients include for example, PEG ester, poloxamer, water-solubleanionic polysaccharide, and carboxymethylcellulose.

Preferably, the abuse deterrent formulation is in the form of a capsule.

The abuse-deterrent formulation is characterized as having at least oneof the properties (a) having a dissolution profile wherein at least 80%of the medicament is released in solution within 45 minutes; (b) thepeak force to expel the abuse-deterrent formulation through a 26 gaugeneedle is about an order of magnitude greater than the peak force toinject a non-abuse deterrent formulation through a 26 gauge needle; (c)the area under the force vs. time curve to expel the abuse-deterrentformulation through a 26 gauge needle is about 4 times greater than thearea under the force vs. time curve to expel a non-abuse-deterrentformulation through a 26 gauge needle, wherein the non-abuse deterrentformulation is a filtered sample; (d) the viscosity of theabuse-deterrent formulation is about three orders of magnitude greaterthan an non-abuse-deterrent formulation, wherein the non-abuse-deterrentformulation is an unfiltered sample; (e) a mixture of theabuse-deterrent formulation and water is not syringeable; (f) less than5 wt % of the abuse-deterrent formulation passes through a 1 mm sieveafter grinding for about 5 minutes; and (g) less than 10% of themedicament is extracted with 10 mL of water from a unit dose of theabuse-deterrent formulation.

In some embodiments, the abuse-deterrent formulation is characterized ashaving at least three or more of the properties (a)-(g). In someembodiments, the abuse-deterrent formulation is characterized as havingat least four or more of the properties (a)-(g). In some embodiments,the abuse-deterrent formulation is characterized as having at least fiveor more of the properties (a)-(g). In some embodiments, theabuse-deterrent formulation is characterized as having at least six ormore of the properties (a)-(g)

The abuse deterrent formulation is orally bioavailable and can have adissolution profile similar to the profile of a non-abuse deterrentformulation. In some embodiments, the abuse-abuse deterrent formulationhas a dissolution profile wherein release of the medicament in solutionis complete within 45 minutes.

In some embodiments, the abuse-abuse deterrent formulation has adissolution profile wherein at least about 93% of the medicament isreleased in solution within 45 minutes. In some embodiments, theabuse-abuse deterrent formulation has a dissolution profile wherein atleast about 80% of the medicament is released in solution within 20minutes. In some embodiments, the abuse-abuse deterrent formulation hasa dissolution profile wherein at least about 80% of the medicament isreleased in solution within 10 minutes. In particular embodiments, theapplication discloses a dextroamphetamine-containing formulation havinga dissolution profile wherein at least about 80% of the medicament isreleased in solution within 45 minutes.

The abuse deterrent formulation is resistant to chemical extraction orinjection. For example, the formulation is resistant to chemicalextraction or injection wherein an abuser extracts the active ingredientof a dosage unit, sometimes in a heated solvent, then swallows orinjects the resulting mixture. For instance, combining the formulationwith a solvent results in a mixture that blocks a syringe or isotherwise uninjectable. In some embodiments, the formulation forms aviscous gel with a solvent making it difficult to draw up in a syringeor expel from a syringe. In other embodiments, the amount of filtrateobtained from the attempted extraction is very little, providing theabuser with an insufficient amount of the desired active ingredient.

In some embodiments, a mixture of the abuse-deterrent formulation andwater is not syringeable. In some embodiments, combining a unit dose ofthe abuse-deterrent formulation and water forms a gel.

In other embodiments, less than 20% of volume can be syringed from amixture of the abuse-deterrent formulation and water. In a furtherspecific embodiment, less than 10% of volume can be syringed from amixture of the abuse-deterrent formulation and water. In anotherembodiment, less than 10% of the medicament is extracted with 10 mL froma unit dose of the abuse-deterrent formulation. In specific embodiments,the temperature of the water is about 90° C. In other embodiments, thetemperature of the water is ambient temperature.

The physical properties of the abuse deterrent formulation detersabusers from grinding or cutting the formulation and then snorting theground material. Upon grinding or a similar physical manipulation, theformulation may become sticky or have a waxy character that preventsforming an inhalable powder or snortable, even in the presence of a flowenhancer such as talc or sodium chloride.

In some embodiments, less than 5 wt % of the abuse-deterrent formulationpasses through a 1 mm sieve after grinding for about 5 minutes. Inspecific embodiments, a flow enhancer is combined with theabuse-deterrent formulation during grinding.

In some embodiments, the abuse-deterrent formulation comprises amedicament, PEG ester, poloxamer, and water-soluble anionicpolysaccharide. In specific embodiments, the PEG ester is polyoxylstearate; the poloxamer is poloxamer 124; and the water-soluble anionicpolysaccharide is gellan gum. In some embodiments, the ratio ofpoloxamer:polysaccharide:PEG ester is about 40:30:30.

In some embodiments, the abuse-deterrent formulation comprisesmedicament, PEG ester, and water-soluble anionic polysaccharide. Inspecific embodiments, the PEG ester is polyoxyl stearate; and thewater-soluble anionic polysaccharide is gellan gum. In further specificembodiments, the ratio of PEG ester:water-soluble anionic polysaccharideis about 70:30.

In yet another embodiment, the abuse-deterrent formulation comprisesmedicament, PEG ester, and carboxymethylcellulose. In specificembodiments, the PEG ester is polyoxyl stearate. In further specificembodiments, the ratio of PEG ester and carboxymethylcellulose is about70:30.

Specifically, the invention provides, an abuse-deterrent formulation,including a medicament, a poloxamer, a water-soluble anionicpolysaccharide, and a PEG ester. The medicament is

or a pharmaceutically acceptable salt thereof.

Alternatively, is the S enantiomer of amphetamine, or a pharmaceuticallyacceptable salt thereof.

Preferably, the medicament is dextroamphetamine, or a pharmaceuticallyacceptable salt thereof.

The pharmaceutically acceptable salt is for example, a sulfate salt. Theunit dose of the medicament in the formulation is from about 10 mg toabout 50 mg. Preferably, the abuse deterrent formulation is in the formof a capsule. The capsule is for example gelatin,

The poloxamer is poloxamer 124. The water-soluble anionic polysaccharideis gellan gum.

The PEG ester is polyoxyl stearate. The ratio of poloxamer:water-solubleanionic polysaccharide:PEG ester is about 40:30:30.

The abuse-deterrent formulation included 33-43 wt % of poloxamer; 24-32wt % of water-soluble anionic polysaccharide; and 24-32 wt % of PEGester.The ratio of poloxamer 124:gellan gum:polyoxyl stearate is about40:30:30.

The poloxamer is Kollisolv P124, the water-soluble anionicpolysaccharide is Kelcogel CGHA, and the PEG ester is Gelucire 48/16.

A preferred formulation includes or the S enantiomer

(dextroamphetamine), or a pharmaceutically acceptable salt as thereof asthe medicament, poloxamer 124, gellan gum, and polyoxyl stearate wherethe ratio of poloxamer 124:gellan gum:polyoxyl stearate is about40:30:30. In some embodiments, the poloxamer 124 is Kollisolv P124, thegellan gum is Kelcogel CGHA, and the polyoxyl stearate is Gelucire48/16.

In some embodiments, at least 80% of the medicament is released insolution within 45 minutes.

In some aspects when the abuse-deterrent formulation and water iscombined a gel is formed.

In other aspects, at least 80% of the medicament is released in solutionwithin 45 minutes.

In a further aspect, the peak force to expel the abuse-deterrentformulation through a 26 gauge needle is at least 8 times greater than apeak force to inject a non-abuse deterrent formulation through a 26gauge needle.

The area under a force vs. time curve to expel the abuse-deterrentformulation through a 26 gauge needle is at least 3 times greater thanthe area under a force vs. time curve to expel a non-abuse-deterrentformulation through a 26 gauge needle, wherein the non-abuse deterrentformulation is a filtered sample.

In yet another aspect the viscosity of the abuse-deterrent formulationis at least about 2 orders of magnitude greater than anon-abuse-deterrent formulation.

In a further aspect, a mixture of the abuse-deterrent formulation andwater is not syringeable.

In another aspect, less than 5 wt % of the abuse-deterrent formulationpasses through a 1 mm sieve after grinding for about 5 minutes.

In some aspects, less than 10% of the medicament is extracted with 10 mLof water from a unit dose of the abuse-deterrent formulation.

Also included in the invention are methods of treatingattention-deficit/hyperactivity disorder (ADHD) in a subject byadministering an abuse deterrent formulation of the invention, where themedicament is an amphetamine such as dextroamphetamine.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention pertains. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice of the present invention, suitable methods and materials aredescribed below. All publications, patent applications, patents, andother references mentioned herein are expressly incorporated byreference in their entirety. In cases of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples described herein are illustrative onlyand are not intended to be limiting.

Other features and advantages of the invention will be apparent from andencompassed by the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows dissolution profiles for Prototype 2.

FIG. 2 shows dissolution profiles for Prototype 3.

FIG. 3 shows dissolution profiles for Prototype 6.

FIG. 4 shows dissolution profiles for Prototype 7.

FIG. 5 shows dissolution profiles for Prototype 10.

FIG. 6 shows extraction data for Prototypes 2, 3, 6, 7 and 10.

FIG. 7 shows an image of Prototype 3 (round 1) following the shakingperiod.

FIG. 8 shows an image of Prototype 7 (round 1) following shaking periodin hot water.

FIG. 9A-B shows images of prototype 2 after grinding (FIG. 9A), andshaking (FIG. 9B).

FIG. 10A-F shows images of the comparator after grinding (FIG. 10A), andthe amount collected on 1 mm sieve (FIG. 10B), 500 μm sieve (FIG. 10C),250 μm sieve. Note: picture labelled 1 mm in error (FIG. 10D), 106 μmsieve (FIG. 10E), and on base (FIG. 10F).

FIG. 11A-B shows images of Prototype 2 after grinding with Talc (FIG.11A), and after shaking capsule contents remain on the 1 mm sieve (FIG.11B).

FIG. 12A-B shows images of Prototype 2 after grinding with SodiumChloride (FIG. 12A), and after shaking (FIG. 12B), where capsulecontents remain mainly on the 1 mm sieve.

FIG. 13A-E shows images of Prototype 2 in ambient Water (FIG. 13A),ambient acetic acid (FIG. 13B), ambient 0.2% Sodium Bicarbonate (FIG.13C), ambient Ethanol (95%) (FIG. 13D), and ambient carbonated softdrink (FIG. 13E).

FIG. 14A-D shows images of the comparator in ambient water (FIG. 14A),ambient 0.2% sodium bicarbonate (FIG. 14B), ambient ethanol (95%) (FIG.14C), and ambient carbonated soft drink (FIG. 14D).

FIG. 15A-B shows images of the comparator and Prototype 2 after crushing(FIG. 15A), and homogenized in hot water (FIG. 15B).

FIG. 16A-B shows images of the filtrate of the comparator (FIG. 16A) andPrototype 2 (FIG. 16B) in hot water and after shaking.

FIG. 17 shows images of crushed comparator, comparator in ambientEthanol (40%), the filtrate and after shaking.

FIG. 18A-B shows images of syringing the comparator (FIG. 18A) andprototype 2 (FIG. 18B) in ambient water with a 26 gauge needle.

FIG. 19A-B shows images of syringing the comparator (FIG. 19A) andprototype 2 (FIG. 19B) in hot water with a 26 gauge needle.

FIG. 20A-D shows images of syringing the comparator in ambient waterwith an 18 G needle (FIG. 20A) and a 0.2 μm nylon filter (FIG. 20B),cotton wool (FIG. 20C), and a cigarette filter (FIG. 20D).

FIG. 21A-D shows images of syringing prototype 2 in ambient water withan 18 G needle (FIG. 21A) and a 0.2 μm nylon filter (FIG. 21B), cottonwool (FIG. 21C), and a cigarette filter (FIG. 21D).

FIG. 22A-D shows images of syringing comparator in hot water with an 18G needle (FIG. 22A) and a 0.2 μm nylon filter (FIG. 22B), cotton wool(FIG. 22C), and a cigarette filter (FIG. 22D).

FIG. 23A-D shows images of syringing prototype 2 in hot water with an 18G needle (FIG. 23A) and a 0.2 μm nylon filter (FIG. 23B), cotton wool(FIG. 23C), and a cigarette filter (FIG. 23D).

FIG. 24A-C shows images of syringing the comparator in ambient waterwith a 20 G needle (FIG. 24A) and a 0.2 μm nylon filter (FIG. 24B), anda cigarette filter (FIG. 24C).

FIG. 25A-B shows images of syringing the comparator (FIG. 25A) andprototype 2 (FIG. 25B) in hot water with a 20 G needle.

FIG. 26A-B shows images of syringing the comparator in ambient waterwith a 23 G needle (FIG. 26A) and a cigarette filter (FIG. 26B).

FIG. 27A-D shows images of syringing comparator in hot water with a 23 Gneedle (FIG. 27A) and a 0.2 μm nylon filter (FIG. 27B), cotton wool(FIG. 27C), and a cigarette filter (FIG. 27D).

FIG. 28A-D shows images of syringing prototype 2 in ambient water withan 18 G needle (FIG. 28A), 20 G needle (FIG. 28B), 23 G needle (FIG.28C), and a 26 G needle (FIG. 28D).

FIG. 29A-D shows images of syringing comparator in hot water with an 18G needle (FIG. 29A), 20 G needle (FIG. 29B), 23 G needle (FIG. 29C), anda 26 G needle (FIG. 29D).

FIG. 30A-D shows images of syringing Prototype 2 in hot water with an 18G needle (FIG. 30A), 20 G needle (FIG. 30B), 23 G needle (FIG. 30C), anda 26 G needle (FIG. 30D).

FIG. 31A-D shows images on manipulating the LD, 10 mL of potable waterwas added to 3 full tablets (FIG. 31A) and (FIG. 31B). These were groundtogether to form a powder in liquid which could be loaded into a syringe(FIG. 31D).

FIG. 32A-D shows images manipulating the ADAIR formulation: (FIG. 32A)the equivalent of six 10 mg ADAIR capsules was aliquoted into a mortarand pestle (FIG. 32B) 20 mL of potable water was added (FIG. 32C) thematerial was ground until homogenous, and (FIG. 32D) a viscous, gel-likematerial was produced.

FIG. 33A-D shows images manipulating the placebo formulation: (FIG. 33A)and (FIG. 33B) 20 mL of water was added to a mortar and pestle, (FIG.33C) these were ground together until homogenous, and (FIG. 33D) aviscous product was obtained.

FIG. 34A-F shows images illustrating set up for the texture analyzersyringability method development. The plungers were removed from 5 mLsyringes and these were back-filled with the material under test (FIG.34A). Air bubbles were then removed to achieve a homogenous fill of >3mL (FIG. 34B). The filled syringe was loaded into the texture analyzersyringe testing rig (FIG. 34C). The plunger was set to 3 mL (FIG. 34D).The needle was attached (FIG. 34E and FIG. 34F). The test was carriedout, moving the forces required to move the syringe plunger from the 3mL to the 2 mL mark (9 mm), expelling material from the needle (whereappropriate).

FIG. 35 is a graph showing texture analyser syringe profiles for themethod development samples: manipulated ADF with 26 G needle (green),manipulated ADF with 18 G needle (dark blue), empty 5 mL syringe 18 G(black), water 5 mL syringe 26 G (light blue), water 5 mL syringe 18 G(red) and empty 5 mL syringe 26 G (pink). The maximum force betweenpoints 1 and 2 is the stiction. The maximum force between points 2 and 3is the plateau force. The maximum force between point 3 and 4 is the endconstraint.

FIG. 36 is a bar chart showing the of average stiction force, plateauforce and end constraint for empty syringes, manipulated placebo (MADF)and water obtained using the texture analyser for 18 G and 26 G needles.

FIG. 37 is a graph showing texture analysis profiles for the emptysyringe 18 G needle (red), empty syringe 26 G needle (blue) and emptysyringe, no needle (black), n=3.

FIG. 38 is a graph showing texture analysis profiles for water 26 Gneedle (dark blue) and water 18 G (light blue), n=3.

FIG. 39 is a graph showing texture analysis profiles for the unfilteredLD through a 26 G needle (n=3). Not that the multiple peaks and troughsare a result of particulates of the crushed tablet causing temporaryblockages to the needle, n=3.

FIG. 40 is a graph showing texture analysis for the unfilteredmanipulated LD using an 18 G needle, n=3.

FIG. 41 is a graph showing texture analysis for manipulated ADAIRunfiltered through a 26 G (green) and 18 G (orange) needle, n=3.

FIG. 42 is a graph showing texture analysis for manipulated placebothrough an 18 G (pink) and 26 G needle (green), n=3.

FIG. 43 is a graph showing texture analysis for manipulated filtered LDthrough an 18 G (green, n=3) and 26 G (red, n=2) needle.

FIG. 44 is a bar chart showing the average peak force recorded for allmanipulated samples measured on the texture analyzer using an 18 Gneedle. Error bars represent standard deviation (n=3).

FIG. 45 is a bar chart showing the average peak force recorded for allmanipulated samples measured on the texture analyzer using a 26 Gneedle. Error bars represent standard deviation (n=3, apart from LDfiltered 26 G where n=2).

FIG. 46 is a bar chart showing the average area under the force vs timecurve (in Ns) recorded for all manipulated samples measured on thetexture analyzer using an 18 G needle. Error bars represent standarddeviation (n=3).

FIG. 47 is a bar chart showing the average area under the force vs timecurve (in Ns) recorded for all manipulated samples measured on thetexture analyzer using a 26 G needle. Error bars represent standarddeviation (n=3, apart from LD filtered 26 G where n=2).

FIG. 48 is a bar chart showing the average peak force recorded forwater, manipulated ADAIR and manipulated, filtered LD samples measuredon the texture analyzer using an 18 G needle. Error bars representstandard deviation (n=3).

FIG. 49 is a bar chart showing the average peak area under the force vstime curve (in Ns), manipulated ADAIR and manipulated, filtered LDsamples measured on the texture analyzer using an 18 G needle. Errorbars represent standard deviation (n=3).

FIG. 50 is a bar chart showing the average peak force recorded forwater, manipulated ADAIR and manipulated, filtered LD samples measuredon the texture analyzer using a 26 G needle. Error bars representstandard deviation (n=3, apart from LD filtered 26 G where n=2).

FIG. 51 is a bar chart showing the average area under the force vs timecurve (in Ns) recorded for water, manipulated ADAIR and manipulated,filtered LD samples measured on the texture analyzer using a 26 Gneedle. Error bars represent standard deviation (n=3, apart from LDfiltered 26 G where n=2).

FIG. 52 is a graph showing texture analysis profiles for water 26 G(dark blue), water 18 G (light blue), filtered LD 18 G (orange) andfiltered LD 26 G (red). Measurements are all in a similar order ofmagnitude. Red shading represents the area under the curve for onerepeat of the LD 18 G.

FIG. 53 is a graph showing texture analysis profiles of water (blue),filtered manipulated LD (red) and manipulated ADAIR (green) fordepressing the plunger of Leur-Lok 5 mL syringe by 9 mm, whilstexpelling the material under test through a 26 G needle.

FIG. 54A-E are graphs showing viscosity and shear stress vs shear ratefor the manipulated LD when unfiltered (FIG. 54A-B) and filtered (FIG.54C-D) compared to a single repeat of water (FIG. 54E).

FIG. 55A-B are graphs showing viscosity and shear stress vs shear ratefor two samples of manipulated ADAIR.

FIG. 56A-B are graphs showing viscosity and shear stress vs shear ratefor two samples of manipulated placebo.

FIG. 57 are graphs showing viscosity vs shear rate for the placeboformulation at 65, 55 and 45° C.

FIG. 58 are graphs showing viscosity vs shear rate for the ADAIRformulation at 65, 55 and 45° C.

FIG. 59 is a graph showing the dissolution of 10 mg or LD in 0.01M HCLon apparatus 1.

FIG. 60 is an image of a chromatogram showing the difference inretention time between the columns.

FIG. 61 is an image of a chromatogram showing 10 mg prototype 1 in 0.01MHCl on Apparatus 1—5 minutes.

FIG. 62 is an image of a chromatogram showing 10 mg prototype 1 in 0.01MHCl on Apparatus 1—10 minutes.

FIG. 63 is an image of a chromatogram showing 10 mg prototype 4 in 0.01MHCl on Apparatus 1—45 Minutes.

FIG. 64 is an image of a chromatogram showing 10 mg prototype 5 in 0.01MHCl on Apparatus 1—45 Minutes.

FIG. 65 is an image of a chromatogram showing 10 mg prototype 6 in 0.01MHCl on Apparatus 1—45 Minutes.

FIG. 66 is a graph showing the comparison of average % releasedissolution profile for Protoype 2 30 mg with LD at 30 DPM.

FIG. 67 : is a graph showing the comparison of average % releasedissolution profile for Prototype 2 30 mg and LD at 30 DPM 0.01M HCLusing Apparatus 3 at SDPM.

FIG. 68 : is a graph showing the average dissolution of 10 mg LD in asize 00 shell n=6 in 0.01M HCL using Apparatus 3 at SDPM using theGemini Column.

FIG. 69 : is a graph showing the comparison of average % release of 10mg ADAIR in 0.01M HCl Apparatus 3 at 5 DPM.

FIG. 70 : is a graph showing the comparison of average % release of 10mg ADAIR in 0.01M HCl Apparatus 3 at 30 DPM with LD at 5 DPM.

FIG. 71 : is a graph showing the dissolution profile of 10 mg ADAIR in0.01M HCl Apparatus 1 duplicate prep at Initial and at 40C 75% RHcompared to that of the LD.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides an abuse-deterrent formulation that is animmediate release formulation and has various barriers to abuse. Inparticular, the formulation deters abuse by preventing insufflation of adrug by crushing, cutting or grinding. The formulation also deters abuseby injection through barriers against syringeability. At the same time,the formulation is compatible with commercial manufacturing processesfor making unit dosages.

The abuse deterrent formulation contains a medicament, which istypically a controlled substance. The controlled substance may targetthe central nervous system and/or may be used to treat psychiatricdisorders such as ADHD. Preferred controlled substance includeamphetamines such as dextroamphetamine. Also included in the inventionor methods of treating ADHD in a subject by administering the an abusedeterrent formulation containing amphetamines such as dextroamphetamine.The subject is a pediatric subject. Alternatively, the subject is anadult.

In specific embodiments, the medicament has a formula

or a pharmaceutically acceptable salt thereof. In further specificembodiments, the medicament is the S enantiomer, or a pharmaceuticallyacceptable salt thereof.

The unit dosed of the medicament, e.g., amphetamine or dextroamphetaminis between about 10-50 mg. For example, the unit dose is 5 mg, 10 mg, 15mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg.

The formulation contains one or more excipients. The excipients areselected to prevent abuse of the medicament.

Suitable abuse deterrent excipients may display one or more of thefollowing properties.

high melting point excipients resistant to heating and that preventinjecting; taste modifiers which prevent covert administration, snortingand dose dumping; water insolubles that are resistant to extraction andthat prevent drink adulteration; waxy excipients that prevent snorting;viscosity modifiers resistant to dissolution and that prevent injectingand dose dumping; low density excipients that prevent drinkadulteration; and dyes that disclose abuse of the pharmaceuticalmedicament.

Exemplary excipients include for example thermosoftening pharmaceuticalbases including waxes, poloxamers, macrogol glycerides, PEGs, glycerolmonooleates or monostearates, PEG esters such as polyoxyl stearate,hydrogenated or partially hydrogenated glycerides and hard fats such asbeeswax, poloxamer 188 poloxamer 124, Gelucires™ polyethylene 6000,glycerol monostearate, hydrogenated palm kernel oil, hydrogenatedcottonseed oil, Softisan™ 138, Gelucire 40/01™, hexadecan-1-ol;Thixotropes such as fumed silica and pulverised attapulgite andviscosity modifiers such as hydroxyl propyl methyl cellulose or Gellangum™ to increase viscosity or the standard pharmaceutical or food gradeoils such as fractionated coconut oil, soyabean oil etc to decreaseviscosity.

Preferably, the abuse deterrent excipients include a poloxamer, awater-soluble anionic polysaccharide and a PEG ester. Preferably, thepoloxamer is poloxamer 124 sucha as Kollisolv. Preferably, the watersoluble anionic polysaccharide is gellan gum such as Kecogel CGHA.Preferably, the PEG ester is polyoxyl stearate such as Gelucire 48/16.

The abuse deterrent formulation may be in a capsule form, such as a hardshell liquid filled capsule. For example, the capsule comprises gelatin.Alternatively, the capsule comprises hydroxypropyl methylcellulose(HPMC), pullalan or other hard shell material.

The formulations of the invention are resistant to chemical extractionor injection, wherein an abuser extracts the active ingredient of adosage unit, sometimes in a heated solvent, then swallows or injects theresulting mixture. For instance, combining the formulation with asolvent results in a mixture that blocks a syringe or is otherwiseuninjectable. In other aspects, the formulations forms a viscous gelwith a solvent making it difficult to draw up in a syringe or expel froma syringe. Alternatively, the amount of filtrate obtained from theattempted extraction is very little, providing the abuser with aninsufficient amount of the desired active ingredient.

In some embodiments, a mixture of the abuse-deterrent formulation andwater is not syringeable. In some embodiments, combining a unit dose ofthe abuse-deterrent formulation and water forms a gel.

An important aspect of the invention is that the medicament of the abusedeterrent formulation performs normally when taken as intended. Forexample, the abuse deterrent formulation is orally bioavailable and hasa dissolution profile similar to the profile of a non-abuse deterrentformulation of the same medicament. In some embodiments, the abuse-abusedeterrent formulation has a dissolution profile wherein release of themedicament in solution is complete within 45 minutes.

Additionally, the abuse deterrent formulation is resistant to chemicalextraction or injection, wherein an abuser extracts the activeingredient of a dosage unit, sometimes in a heated solvent, thenswallows or injects the resulting mixture. For instance, combining theformulation with a solvent results in a mixture that blocks a syringe oris otherwise uninjectable. In some embodiments, the formulation forms aviscous gel with a solvent making it difficult to draw up in a syringeor expel from a syringe. In other embodiments, the amount of filtrateobtained from the attempted extraction is very little, providing theabuser with an insufficient amount of the desired active ingredient.

The physical properties of the abuse deterrent formulation detersabusers from grinding or cutting the formulation and then snorting theground material. Upon grinding or a similar physical manipulation, theformulation may become sticky or have a waxy character that preventsforming an inhalable powder or snortable, even in the presence of a flowenhancer such as talc or sodium chloride.

Accordingly, the invention provides an abuse-deterrent formulationhaving a medicament; and at least two excipients selected from PEGester, poloxamer, water-soluble anionic polysaccharide, andcarboxymethylcellulose. In some aspects, the abuse-deterrent formulationis characterized as having at least one of the properties selected fromthe group consisting of (a) having a dissolution profile wherein atleast 80% of the medicament is released in solution within 45 minutes;(b) the peak force to expel the abuse-deterrent formulation through a 26gauge needle is about an order of magnitude greater than the peak forceto inject a non-abuse deterrent formulation through a 26 gauge needle;(c) the area under the force vs. time curve to expel the abuse-deterrentformulation through a 26 gauge needle is about 4 times greater than thearea under the force vs. time curve to expel a non-abuse-deterrentformulation through a 26 gauge needle, wherein the non-abuse deterrentformulation is a filtered sample; (d) the viscosity of theabuse-deterrent formulation is about three orders of magnitude greaterthan an non-abuse-deterrent formulation, wherein the non-abuse-deterrentformulation is an unfiltered sample; (e) a mixture of theabuse-deterrent formulation and water is not syringeable; (f) less than5 wt % of the abuse-deterrent formulation passes through a 1 mm sieveafter grinding for about 5 minutes; and (g) less than 10% of themedicament is extracted with 10 mL of water from a unit dose of theabuse-deterrent formulation.

Milling

Milling or grinding involves the physical break down of a dosage unitand can be accomplished by a variety of methods. Grinding can beaccomplished by force on a dosage unit by a solid surface. for instance,the use of a coffee grinder, a mortar and pestle, or a spoon and a bowlmay be involved. In some embodiments, the abuse-deterrent formulationbecomes a paste when ground.

In some embodiments, the disclosed abuse-deterrent formulation resiststhe formation of an inhalable powder even when ground with a flowenhancer. Non-limiting examples of a flow enhancer, include talc andsodium chloride. In some embodiments, the abuse-deterrent formulationbecomes a paste when ground with a flow enhancer.

In some embodiments, less than 5 wt %, 4 wt %, 3 wt %, 2 wt %, 1 wt %,or 0.5 wt % of the abuse-deterrent formulation passes through a 1 mmsieve after grinding for about 5 minutes.

In some embodiments, less than 5 wt %, 4 wt %, 3 wt %, 2 wt %, 1 wt %,or 0.5 wt % of the abuse-deterrent formulation passes through a 0.5 mmsieve after grinding for about 5 minutes.

In some embodiments, more than 95 wt %, 96 wt %, 97 wt %, 98 wt %, or 99wt % of the abuse deterrent formulation is retained on a 1 mm sieveafter grinding for about 5 minutes. In some embodiments, more than 95 wt%, 96 wt %, 97 wt %, 98 wt %, or 99 wt % of the abuse deterrentformulation is retained on a 0.5 mm sieve after grinding for about 5minutes.

Extraction/Syringability

In some embodiments, the combination of the abuse-deterrent formulationand a solvent results in a difficult to filter mixture. In someembodiments, combination of the abuse-deterrent formulation and asolvent is not syringable because it forms a viscous gel.

In some embodiments, the formulation is combined with about 10 mL ofsolvent, and less than 50%, less than 40%, less than 30%, less than 20%,or less than 10% of the resulting solution is drawn up into a syringe.

In some embodiments a unit dose of the formulation is extracted withabout 10 mL of solvent and less than 50%, less than 40%, less than 30%,less than 20%, or less than 10% of the medicament is recovered. In someof the foregoing embodiments, one or more unit doses of theabuse-deterrent formulation is extracted with 10 mL of solvent.

In particular embodiments, the solvent is water, or 40% ethanolsolution. Water may be ambient temperature, boiling, or may have atemperature of 90-95° C.

In some of the foregoing embodiments, the solution is filtered whilebeing drawn into the syringe. Examples of filters include a 0.2 micronfilter, a 5.0 micron wheel filter, a wad of cotton, a cigarette filtertip, a cotton swab, a tampon, a fabric material, or any common materialavailable in a household capable of being used as a filter.

The syringe may be attached to a 26, 23, or 18 gauge needle. A 26 gaugeneedle is the preferred size for abusers since it is easy to insert andremove, is more comfortable to use, and results in less damage to theskin and blood vessels. Larger bore needles may not be as comfortable touse, and may damage the skin and blood vessels especially after repeatedusage. In specific embodiments, the abuse-deterrent formulation isexpelled through a 26 gauge needle.

In specific embodiments, less than 10% of dextroamphetamine is recoveredfrom extraction of a unit dose of the abuse deterrent formulation with10 mL of ambient temperature water. In specific embodiments, extractionof a unit dose of the abuse deterrent formulation with 10 mL of heatedwater is not filterable. In specific embodiments, less than 15%, lessthan 10% or less than 5% of dextroamphetamine is extracted from a unitdose of the abuse deterrent formulation with 10 mL of water. In specificembodiments, less than 15%, less than 10% or less than 5% ofdextroamphetamine is extracted and filtered from a unit dose of theabuse deterrent formulation with 10 mL of water.

In specific embodiments, less than 5%, or less than 2.5% ofdextroamphetamine is extracted from a unit dose of the abuse deterrentformulation with 5 mL of water using a 26 gauge needle. In specificembodiments, less than 20% or less than 15% of dextroamphetamine isextracted from a unit dose of the abuse deterrent formulation with 5 mLof water using a 23 gauge needle. In specific embodiments, less than 30%or less than 25% of dextroamphetamine is extracted from a unit dose ofthe abuse deterrent formulation with 5 mL of water using a 20 gaugeneedle. In specific embodiments, less than 50% of dextroamphetamine isextracted from a unit dose of the abuse deterrent formulation with 5 mLof water using an 18 gauge needle.

In specific embodiments, less than 5% of dextroamphetamine is extractedfrom a unit dose of the abuse deterrent formulation with 5 mL of 90-95°C. water using a 26 or 23 gauge needle. In specific embodiments, lessthan 20% of dextroamphetamine is extracted from a unit dose of the abusedeterrent formulation with 5 mL of 90-95° C. water using a 20 or 18gauge needle.

In specific embodiments less than 25% of dextroamphetamine is extractedand filtered from a unit dose of the abuse deterrent formulation with 5mL of 0.2% sodium bicarbonate solution. In specific embodiments, a unitdose of the abuse-deterrent formulation comprising dextroamphetamineforms an unfilterable gel with 2 mL of 0.2% sodium bicarbonate solution.In specific embodiments, a unit dose of the abuse-deterrent formulationcomprising dextroamphetamine forms an unfilterable gel with 5 mL of 0.2%sodium bicarbonate solution.

Application of Heat

In some instances, abusers of a controlled substance heat the substanceand inject the resulting liquid. Injection of the melted abuse deterrentformulation disclosed in this application is unsuccessful because thedrug product solidifies when removed from a heat source and drawn intothe needle.

In some embodiments, the abuse deterrent formulation has a meltingtemperature above 60° C. In some embodiments, the abuse deterrentformulation has a melting temperature of about 70° C.

Dissolution

Descriptions of investigating the dissolution profile of abuse-deterrentformulations and comparators, and dissolution profile data may be foundin the Examples.

In some embodiments, the abuse-abuse deterrent formulation has adissolution profile wherein at least about 93% of the medicament isreleased in solution within 45 minutes. In some embodiments, theabuse-abuse deterrent formulation has a dissolution profile wherein atleast about 80% of the medicament is released in solution within 20minutes. In some embodiments, the abuse-abuse deterrent formulation hasa dissolution profile wherein at least about 80% of the medicament isreleased in solution within 10 minutes. In particular embodiments, theinvention provides a dextroamphetamine-containing formulation having adissolution profile wherein at least about 80% of the medicament isreleased in solution within 45 minutes.

Viscosity

Viscosity measurements may be used to characterize the abuse-deterrentformulation and provides valuable comparative data tonon-abuse-deterrent formulations. Such descriptions of methodology anddata relating to manipulated formulations are provided in the Examples.A higher viscosity of a manipulated formulations indicates increaseddifficulty in injecting, making it more difficult for an abuser to usethe formulation. In some embodiments, the viscosity of theabuse-deterrent formulation is about three orders of magnitude greaterthan a non-abuse deterrent formulation. In some embodiments, theviscosity of the abuse-deterrent formulation is about two orders ofmagnitude greater than a non-abuse deterrent formulation. In some of theforegoing embodiments, the viscosity of the non-abuse deterrentformulation is measured from an unfiltered sample.

In some embodiments, the viscosity of the abuse-deterrent formulation isgreater than 6000 cP. In some embodiments, the viscosity of theabuse-deterrent formulation is greater than 5000 cP. In someembodiments, the viscosity of the abuse-deterrent formulation is greaterthan 4000 cP. In some embodiments, the viscosity of the abuse-deterrentformulation is greater than 3000 cP.

Injectability

The peak force and the area under the force vs. time curve to expelabuse-deterrent formulations may be used to characterize the formulationand provide valuable comparative data to a non-abuse-deterrentformulation. Descriptions of methodology to compare the required forcesto expel abuse-deterrent formulations and comparators are described inExample 4. The data demonstrates that a greater force is required toexpel manipulated abuse-deterrent formulation through a 26 gauge needlethan that for the manipulated filtered comparator through the sameneedle size. This supports a more abuse-deterrent formulation withrespect to syringeability than a comparable non-abuse deterrentformulation.

In some embodiments, the average peak force to expel the abuse deterrentformulation through a 26 gauge needle is about 10 times, 9 times, 8times, 7 times, 6 times, 5 times, or 4 times greater than the averagepeak force to inject a non-abuse deterrent formulation through a 26gauge needle. In some embodiments, the average peak force to expel theabuse deterrent formulation through a 26 gauge needle is greater than 40N, 35 N, 30 N, 25 N, or 20 N.

In some embodiments, the average area under the force vs. time curve toexpel the abuse-deterrent formulation through a 26 gauge needle is 4times, 3, times, or 2 times greater than the average area under theforce vs. time curve to expel a non-abuse-deterrent formulation througha 26 gauge needle. In some embodiments, the average area under the forcevs. time curve is greater than 250 Ns, 200 Ns, 150 Ns, or 100 Ns.

Specific Formulations

In some embodiments, the abuse-deterrent formulation comprises at leasttwo excipients selected from Kollisolv P124, Kolliphor EL, KolliphorRH40, Tween 20, Gelucire 48/16, Gelucire 44/14, Super refined Corn Oil,Aerosil 200, Luxura, Xantural 75, Kelcogel CGHA, CMC 7H3SF, MethocelA4CP, Gelatin Type B 220 Bloom, and PEG6000.

In some embodiments, the abuse-deterrent formulation comprises amedicament, PEG ester, poloxamer, and water-soluble anionicpolysaccharide. In specific embodiments, the PEG ester is polyoxylstearate; the poloxamer is poloxamer 124; and the water-soluble anionicpolysaccharide is gellan gum. In some embodiments, the ratio ofpoloxamer:polysaccharide:PEG ester is about 40:30:30.

In some embodiments, the abuse-deterrent formulation comprisesmedicament, PEG ester, and water-soluble anionic polysaccharide. Inspecific embodiments, the PEG ester is polyoxyl stearate; and thewater-soluble anionic polysaccharide is gellan gum. In further specificembodiments, the ratio of PEG ester:water-soluble anionic polysaccharideis about 70:30.

In yet another embodiment, the abuse-deterrent formulation comprisesmedicament, PEG ester, and carboxymethylcellulose. In specificembodiments, the PEG ester is polyoxyl stearate. In further specificembodiments, the ratio of PEG ester and carboxymethylcellulose is about70:30.

In some embodiments, the abuse-deterrent formulation comprises amedicament, Kollisolv P124, Kelcogel CGHA, and Gelucire 48/16. Infurther specific embodiments, the ratio of Kollisolv P124, KelcogelCGHA, and Gelucire 48/16 is about 40:30:30.

In some embodiments, the abuse-deterrent formulation comprises amedicament, Gelucire 48/16 and Kelcogel CGHA. In further specificembodiments, the ratio of Gelucire 48/16 and Kelcogel CGHA is about70:30.

In some embodiments, the abuse-deterrent formulation comprises amedicament, Kolliphor EL and CMC 7H3SF. In further specific embodiments,the ratio of Kolliphor EL and CMC 7H3SF is about 70:30.

In any of the foregoing embodiments, the medicament is a controlledsubstance. The controlled substance may target the central nervoussystem and/or may be used to treat psychiatric disorders. Preferably,the controlled substance is an amphetamine, or a pharmaceuticallyacceptable salt thereof. More preferably, the medicament isdextroamphetamine, or a pharmaceutically acceptable salt thereof.

The use of the term “about” includes and describes the value orparameter per se. For example, “about x” includes and describes “x” perse. In some embodiments, the term “about” when used in association witha measurement, or used to modify a value, a unit, a constant, or a rangeof values, refers to variations of +/−5%, or +/−10%.

“Amphetamine” as used herein has the formula:

“Dextroamphetamine” as used herein is the S enantiomer of amphetamineand has the formula:

In some embodiments, the abuse-deterrent formulation comprises one ormore medicaments selected from the group consisting of dextroamphetaminesaccharate, amphetamine aspartate, dextroamphetamine sulfate, andamphetamine sulfate. In some embodiments, the abuse-deterrentformulation comprises two medicaments selected from the group consistingof dextroamphetamine saccharate, amphetamine aspartate,dextroamphetamine sulfate, and amphetamine sulfate. In some embodiments,the medicament is dextroamphetamine sulfate.

In preferred embodiments the abuse-deterrent formulation, includes amedicament, a poloxamer, a water-soluble anionic polysaccharide, and aPEG ester. The medicament is

or a pharmaceutically acceptable salt thereof.

Alternatively, is the S enantiomer of amphetamine, or a pharmaceuticallyacceptable salt thereof such as dextroamphetamine. The unit dose of themedicament in the formulation is from about about 10 mg to about 50 mg,The abuse deterrent formulation is in the form of a capsule. The capsuleis for example gelatin. The poloxamer is poloxamer 124. Thewater-soluble anionic polysaccharide is gellan gum. The PEG ester ispolyoxyl stearate. The ratio of poloxamer:water-soluble anionicpolysaccharide:PEG ester is about 40:30:30. The abuse-deterrentformulation included 33-43 wt % of poloxamer; 24-32 wt % ofwater-soluble anionic polysaccharide; and 24-32 wt % of PEG ester.Theratio of poloxamer 124:gellan gum:polyoxyl stearate is about 40:30:30.The poloxamer is Kollisolv P124, the water-soluble anionicpolysaccharide is Kelcogel CGHA, and the PEG ester is Gelucire 48/16.

A further preferred formulation includes

or the S enantiomer (dextroamphetamine), or a pharmaceuticallyacceptable salt as thereof as the medicament, poloxamer 124, gellan gum,and polyoxyl stearate where the ratio of poloxamer 124:gellangum:polyoxyl stearate is about 40:30:30. In some embodiments, thepoloxamer 124 is Kollisolv P124, the gellan gum is Kelcogel CGHA, andthe polyoxyl stearate is Gelucire 48/16.

Other Embodiments

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims.

EXAMPLES

The following examples are provided to further aid in understanding theembodiments disclosed in the application, and presuppose anunderstanding of conventional methods well known to those persons havingordinary skill in the art to which the examples pertain. The particularmaterials and conditions described hereunder are intended to exemplifyparticular aspects of embodiments disclosed herein and should not beconstrued to limit the reasonable scope thereof.

Example 1: Prototypes 1-10

The examples herein describe ten immediate release abuse deterrentformulations of dextroamphetamine sulfate.

Materials & Equipment

Excipients and Drug Substance

The excipient and manufacturer's name used in these studies are detailedin Table 1.

TABLE 1 Batch details for excipients and drug substance used inpreformulation work. Material Manufacturer Kollisolv P124 BASF KolliphorEL BASF Kolliphor RH40 BASF Tween 20 Croda Gelucire 48/16 GattefosseGelucire 44/14 Gattefosse Super refined corn oil Croda Aerosil 200Evonik Luxura Arthur Branwell and Co. Xantural 75 Kelco Kelcogel CGHAKelco Methocel A4C P Colorcon CMC 7H3SF ASHLAND PEG6000 RenexDextroamphetamine Sulfate Cambrex

Capsule Shells

The capsule shells used for the capsule shell compatibility are detailedin Table 2.

TABLE 2 Batch details for the capsules used in capsule shellcompatibility work. Material Manufacturer Conisnap size 0 white Capsugelgelatin capsules VCaps Plus size 0 white Capsugel HPMC shells

Banding Materials

The raw material and manufacturer's name used in these studies aredetailed in Table 3.

TABLE 3 Batch details for components of banding solutions. MaterialManufacturer Sterile water for irrigation Fresenius Kabi Ltd. Gelatin220 Bloom Gelita EtOH 99% VWR Pharmacoat 603 Shin-EtsuMethods

Preparation of Bulk Mixes

Prototype formulations were prepared on a 30 g scale with 5.455% w/w API(for a target dose of 30 mg per capsule). Excipient ratios are outlinedin Table 4. Kolliphor RH40 was heated in an oven at 50° C. prior todispensing. Prototypes 1, 2, 6, 7, 9 and 10 were mixed and filled atroom temperature. Prototypes 3, 4 and 5 were heated to between 45-55° C.to melt the PEG and Gelucire before mixing and filling. Prototype 8 wasmixed and filled at 75-85° C. Excipients were blended together by vortexmixing prior to dispensing the API. Following the API dispense, allprototypes were briefly vortex mixed again to wet the API. The prototypebulk mixes were then high shear mixed for 1 minute using a Silversonmixer.

TABLE 4 Ratio of excipients in the ten prototype formulations. Prototype# Excipients 1 Kollisolv P124:Luxura (60:40) 2 Kollisolv P124:KelcogelCGHA (70:30) 3 Gelucire 48/16:Kelcogel CGHA (70:30) 4 KolliphorRH40:Kelcogel CGHA (60:40) 5 Gelucire 48/16:CMC7H3SF (60:40) 6 KolliphorEL:Xantural 75 (60:40) 7 Kolliphor EL:CMC 7H3SF (60:40) 8 Gelucire48/16:PEG6000:Xantural 75 (20:40:40) 9 Tween 20:Aerosil 200:Kelcogel(58:2:40) 10 Corn oil:Kolliphor EL:Methocel A4CP (40:30:30)

Prototypes 9 and 10 were adjusted with the addition of Tween 20 or cornoil, respectively, to improve handlability and filling. This resulted insub-potent capsules.

Capsule Filling and Banding

Bulk mixes were degassed in a vacuum chamber prior to filling.Thermosoftening prototypes were degassed after heating in a fan oven.The bulk mixes were filled by syringe into gelatin and HPMC capsules ata target weight of 550 mg (±7.5%). Thermosoftening materials were keptwarm using a water bath for the duration of filling. Filled capsuleswere banded using the appropriate banding solution (gelatin or HPMC) andleft to dry on trays overnight.

Capsule Shell Compatibility Study

Following band drying, the capsules were spread onto witness paper andsubjected to a vacuum challenge for 20 min at −22.5 “Hg. Any capsulesfound to be leaking were removed from the batch and the remainder wasexamined for signs of embrittlement or cracking. After providingcapsules to Analytical Development, the remaining capsules from eachbatch were placed in amber glass jars, sealed with paraffin film andincubated in a stability cabinet at 40° C./75% RH for two weeks. Afterthis time the capsules were equilibrated to room temperature and thenexamined for signs of embrittlement.

Dissolution

Preliminary dissolution tests were carried out on Prototypes 1-10 on USPApparatus III (Table 5). Prototypes 1 and 4 were tested in triplicate.The remainder were analyzed in duplicate or singly. 2 mL samples wereinjected into the system without further sample preparation. The HPLCconditions for dissolution analysis involve an Agilent Eclipse XDB-C184.6 mm×250 mm (5 μm) column, a flow rate of 1.5 mL/min, a columntemperature of 40° C., an injection volume of 100 μL, UV detection at210 nm, room temperature autosampling, and a mobile phase of 1.1 gsodium 1-heptanesulfonate in 575:25:400 Water:Acetic Acid:Methanol atpH3.3.

TABLE 5 Dissolution method using USP apparatus III. Media: 0.01MHydrochloric Acid Media Volume: 250 mL Time points: 5, 10, 15, 20, 30and 45 minutes Sample Volume: 2 mL, injected without further sample prepDip rate: 30 dpm Mesh Screen Size: 840 μm Filtration: 35 μm probefilters

Viscosity

Viscosity assessments were carried out on a Brookfield DV-III UltraProgrammable Rheometer operating with Rheocalc v3.3 Build 49.0(Brookfield Labs, 1999) and spindle CP-52. The instrument was calibratedat 25° C. with 5000 cP viscosity standard (RRM5907, batch 110514,Brookfield, expiry 10 May 2016). A suitable ramp of rotations per minute(rpm) was established prior to each measurement. Due to analyticalissues related to very high viscosity, samples were analyzed at 50° C.,apart from 1003/057/08 which was analyzed at 80° C.

Results and Discussion

Preparation of Bulk Mixes

The theoretical quantities, actual dispensed quantities, actualexcipient ratios and subsequent capsule doses are detailed in Table 6 toTable 15 below. Following preparation, bulk mixes were each high shearmixed for 1 minute. Temperatures before and after high shear wererecorded and detailed in Table 16. At the bulk mix preparation stage,Prototypes 9 and 10 were found to be too viscous to be high shear mixedeffectively and so additional aliquots of Tween 20 and corn oil,respectively, were added until a processable mix was obtained. Note thatthe quantity of API was not adjusted at this point (22.3 and 22.9 mg percap, respectively). Prototype 4 was also found to have very highviscosity at this point however it could still be mixed without issueand filled by syringe, and therefore the mix was not adjusted.

TABLE 6 Prototype 1 theoretical and actual components. KollisolvP124:Luxura 60:40 Actual Actual ratio of % (w/w) Quantity (g) dispensedBalance excipients Potency Dose per Theoretical Theoretical weight (g)ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6362 EI/171 5.5 30.0Kollisolv 56.7270 17.0181 17.0672 EI/043 60.2 124 Luxura 37.8180 11.345411.2914 EI/043 39.8 Total 100.0000 30.0000 100.0

TABLE 7 Prototype 2 theoretical and actual components. KollisolvP124:Kelcogel CGHA 70:30 Actual Actual ratio of % (w/w) Quantity (g)dispensed Balance excipients Potency Dose per Theoretical Theoreticalweight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6311 EI/1715.4 29.9 Kollisolv 66.1815 19.85445 19.8186 EI/043 69.9 P124 Kelcogel28.3635 8.50905 8.5305 EI/043 30.1 CGHA Total 100.0000 30.0000 100.0

TABLE 8 Prototype 3 theoretical and actual components. Gelucire48/16:Kelcogel CGHA 70:30 Actual Actual ratio of % (w/w) Quantity (g)dispensed Balance excipients Potency Dose per Theoretical Theoreticalweight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6324 EI/1715.4 29.9 Gelucire 66.1815 19.85445 19.8835 EI/043 70.1 48/16 Kelcogel28.3635 8.50905 8.4982 EI/043 29.9 CGHA Total 100.0000 30.0000 100.0

TABLE 9 Prototype 4 theoretical and actual components. KolliphorRH40:Kelcogel CGHA 60:40 Actual Actual ratio of % (w/w) Quantity (g)dispensed Balance excipients Potency Dose per Theoretical Theoreticalweight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6335 EI/1715.4 29.9 Kolliphor 56.7270 17.0181 17.0153 EI/043 59.9 RH40 Kelcogel37.8180 11.3454 11.3702 EI/043 40.1 CGHA Total 100.0000 30.0000 100.0

TABLE 10 Prototype 5 theoretical and actual components. Gelucire48/16:CMC 7H3SF 60:40 Actual Actual ratio of % (w/w) Quantity (g)dispensed Balance excipients Potency Dose per Theoretical Theoreticalweight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6288 EI/1715.4 29.8 Gelucire 56.7270 17.0181 17.0637 EI/043 60.0 48/16 CMC 37.818011.3454 11.3576 EI/043 40.0 7H3SF Total 100.0000 30.0000 100.0

TABLE 11 Prototype 6 theoretical and actual components. KolliphorEL:Xantural 75 60:40 Actual Actual ratio of % (w/w) Quantity (g)dispensed Balance excipients Potency Dose per Theoretical Theoreticalweight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6291 EI/1715.4 29.9 Koliphor 56.7270 17.0181 17.0294 EI/043 60.0 EL Xantural 7537.8180 11.3454 11.3454 EI/043 40.0 Total 100.0000 30.0000 100.0

TABLE 12 Prototype 7 theoretical and actual components. Kolliphor EL:CMC7H3SF 60:40 Actual Actual ratio of % (w/w) Quantity (g) dispensedBalance excipients Potency Dose per Theoretical Theoretical weight (g)ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6346 EI/171 5.4 29.9Kolliphor 56.7270 17.0181 17.0465 EI/043 60.0 EL CMC 37.8180 11.345411.3517 EI/043 40.0 7H3SF Total 100.0000 30.0000 100.0

TABLE 13 Prototype 8 theoretical and actual components. Gelucire48/16:PEG6000:Xantural 75 (20:40:40) Bulk mix Actual ratio of quantitydispensed Balance excipients Potency Dose per % (w/w) theoretical (g)weight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.6365 1.6412 EI/1715.5 30.0 Gelucire 18.9090 5.6727 5.6639 EI/043 19.9 48/16 PEG 600037.8180 11.3454 11.3910 EI/043 40.1 Xantural 75 37.8180 11.3454 11.3505EI/043 40.0 Total 100.0000 30.0000 100.0

TABLE 14 Prototype 9 theoretical and actual components*. Tween20:Aerosil:Kelcogel (58:2:40) Actual Actual ratio of % (w/w) Quantity(g) dispensed Balance excipients Potency Dose per TheoreticalTheoretical weight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.63651.6382 EI/171 4.1 21.7 Tween 20 54.8361 16.4508 27.9073 EI/043 70.1Aerosil 1.8909 0.5673 0.5684 EI/043 1.4 Kelcogel 37.8180 11.3454 11.3493EI/043 28.5 Total 100.0000 30.0000 100.0 Note: Additional carrier addeddue to processing issues. Note API potency of 4.1% and subsequentnominal lowered dose of 21.7 mg*

TABLE 15 Prototype 10 theoretical and actual components*. Cornoil:Kolliphor EL:Methocel A4CP (40:30:30) Actual Actual ratio of % (w/w)Quantity (g) dispensed Balance excipients Potency Dose per TheoreticalTheoretical weight (g) ID (% w/w) (% w/w) cap (mg) API 5.4550 1.63651.6353 EI/171 4.2 22.9 Corn oil 37.8180 11.3454 20.6441 EI/043 54.8Kolliphor 28.3635 8.5091 8.5250 EI/043 22.6 EL Methocel 28.3635 8.50918.5052 EI/043 22.6 A4CP Total 100.0000 30.0000 100.0 Note: Additionalcarrier added due to processing issues. Note API potency of 4.2% andsubsequent nominal lowered dose of 22.9 mg*

TABLE 16 High shear temperatures. Prototype Temperature prior toTemperature following # Batch number high shear (° C.) high shear (° C.)1 1003/057/01 21.5 31.1 2 1003/057/02 21.5 26.4 3 1003/057/03 49.7 43.14 1003/057/04 54.6 52.9 5 1003/057/05 45.3 42.0 6 1003/057/06 21.4 32.37 1003/057/07 21.5 31.7 8 1003/057/08 81.6 79.6 9 1003/057/09 28.8 30.010 1003/057/10 22.0 30.2Capsule Filling and Banding

The highly viscous nature of ADFs (and the presence of surfactants) canresult in challenges during degassing, particularly on bench scaleequipment where stirring, heating and degassing cannot be performed inparallel. On scale up this problem is less significant in jacketedmixing vessels, which can be stirred with an applied vacuum andregulated temperature. Formulations 1, 4 and 7 were particularlychallenging due to high viscosity. It is recommended that large mixingvessels (relative to the scale of the bulk mix) are used moving forward,so as to allow ample headspace for bubbles to expand and burst freelyduring degassing.

The formulations were filled into size 0 gelatin and HPMC capsules byhand using syringes to a target weight of 550 mg (±7.5%). It waschallenging, but possible, to fill all of the formulations with thistechnique. Prototypes 1 and 7 proved to be more challenging and it wasexpected that these may not fill well on the semi-automatic Hibarcapsule filling machine without modification. Prototype 4 isthermosoftening however, and although this was challenging to fill byhand, this may be easier to handle in a heated hopper.

Following filling, capsules were banded with or gelatin banding solutionusing a bench scale semi-automatic Qualiseal banding machine, and leftto cure in ambient laboratory conditions overnight.

Dissolution

Prototypes 1-10 were subjected to the dissolution apparatus and thenanalyzed by HPLC at the 45 minute mark. Table 18 summarizes the initialdissolution results at 45 minutes.

Although prototype 1 samples appeared visually dissolved within 45minutes, challenges occurred during HPLC analysis of these samples(column blockages after a few injections). A simple sample treatment ofcentrifuging the HPLC sample vials followed by re-injection at a higherneedle height was investigated but again, the HPLC column became blockedquickly and the complete data set could not be acquired. Further HPLCmethod development would be required if this prototype is taken forward.

For prototype 2, 99.5% release was achieved afer 45 min.

Despite residue remaining in the cylinders for prototype 3, 100.4%release was measured at 45 min.

A significant amount of foaming was observed for prototype 4, whichoverspilled from the dissolution apparatus and therefore quantitativedata was not reported. Again, further method development would berequired for these capsules if the prototype is chosen for progression,and the addition of an anti-foaming agent would be required.

For prototype 5, a significant amount of residue remained at the end ofthe dissolution test, and low release (31.3% and 25.9%) was measuredafter 45 min.

Prototype 6 had low release at 45 min (59.0% and 65.5%) but some residueremained at the end of the test. It is anticipated that reducing theconcentration of Xantural 75 in the formulation may reduce thepersistance of the residue and improve release going forward.

Prototype 7 appeared not to have fully dissolved, with a gel-likeresidue remaining, but a release of 94.6% was measured at 45 min.

Poor dissolution of prototype 8 was measured after 45 min (20.3, 28.9)with a capsule-shaped plug remaining at the end of the test.

Finally, prototypes 9 and 10 were sub-potent due to the addition offurther carrier excipients during compounding. When adjusting for this,release of 107.0% and 101.4% were measured for prototypes 9 an 10,respectively.

TABLE 18 Initial dissolution results for prototype formulations ingelatin shells. Prototype Release at 45 min # (% Label Claim)Observations 1 N/A Visually fully dissolved within 45 minutes. 2  99.5First breach noted at 2 minutes, at 3-4 minutes a dense suspension wasnoted to have formed throughout the moving cylinder. Small amounts ofcapsule remained but visually, full dissolution had occurred by 45minutes. 3 100.4 Capsule noted to be stuck to side of cylinder at 1minute. Capsule breached at 2 minutes. At 10 minutes a large residue ofcapsule remained along with a fine suspension in the cylinder. Visually,at 45 minutes only a small residue of capsule remained. 4 N/A Firstbreach noted at 2 minutes, at 3-4 minutes a dense suspension was notedto have formed throughout the moving cylinder. Small amounts of capsuleremained but visually, full dissolution had occurred by 7 minutes.Surfactant bubbling noted. 5 31.3, 25.9 A small amount of bubbling wasobserved during the test and a significant residue remanined at 45minutes. 6 59.0, 65.5 A small amount of bubbling was observed during thetest and a gel-like residue remanined at 45 minutes. 7  94.6 Firstbreach noted at 2 minutes, at around 10 minutes, the capsule contentswere noted to have flattened against the mesh. At 30 minutes the capsulecontents appeared to be dissolved, but when the cylinder was examined atthe end of the test a clear residue was noted. 8 20.3, 28.9 A capsuleshaped residue remained at 45 minutes. 9 107.0 First breach noted at 2minutes, at 3-4 minutes a dense suspension was noted to have formedthroughout the moving cylinder. Small amounts of capsule remained butvisually, full dissolution had occurred by 7 minutes. Surfactantbubbling noted. 10 101.4 First breach noted at 2 minutes, visually.Complete dissolution appeared to have occurred by 10 minutes.

Viscosity

Preliminary viscosity measurements were attempted for all ten prototypeformulations. Viscosity testing of formulations was carried out at 50°C. rather than 25° C. due to very viscous nature of samples. Prototype 8was examined at 80° C. due to presence of PEG6000.

In general, the prototypes were found to display shear-thinningproperties (reduced viscosity on increased applied shear), which istypical of ADFs. Prototype 1 displayed very high viscosity compared tothe rest of the samples which were analyzed, and could only be examinedover a very small range of low speeds (Table 19). Prototypes 2 and 3displayed viscosities in a similar order of magnitude to each other,over a similar speed ramp (Table 20 and 21). Prototypes 8 and 9 hadsimilar viscosities to 2 and 3 at the high end of the speed ramp (Table23 and 24), but with a greater viscosity than 2 and 3 at low rpm,suggesting higher viscosity on standing, with a greater degree ofthinning upon the application of shear. The viscosity of prototype 6remained higher than 2, 3, 6 and 9 for the duration of the speed ramp(Table 22).

Prototypes 4 and 7 proved challenging to analyze, and a suitable methodcould not be established with the small volume of sample available.Prototype 4 was grainy, with low cohesive properties, meaning it lostits fluid characteristics easily upon attempts at analysis. Prototype 7was very excessively viscous and it is anticipated that this would needto be addressed by modification of the excipient ratios in the nextround of development. An insufficient amount of prototype 5 remainedafter capsule filling to carry out the viscosity assessment on thisprototype. Finally, prototype 10 proved challenging to analyze. Moreextensive method development and a larger sample size would be requiredto obtain useful rheological data on prototype 10.

TABLE 19 Prototype 1 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 7352202.0 0.01 74.1 2 3671140.0 0.02 74.0 32437504.6 0.03 73.7 4 1818206.5 0.04 73.3 5 2381280.0 0.03 72.0 63507427.0 0.02 70.7 7 6925556.0 0.01 69.8

TABLE 20 Prototype 2 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 4709.64 7.50 35.6 2 3175.04 15.00 48.0 32742.88 22.50 62.2 4 2387.89 30.00 72.2 5 2632.64 22.50 59.7 6 2877.3815.00 43.5 7 3651.30 7.50 27.6

TABLE 21 Prototype 3 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 6330.24 5.00 31.9 2 4613.73 10.00 46.5 34028.33 15.00 60.9 4 3715.79 20.00 74.9 5 3995.26 15.00 60.4 6 4613.7310.00 46.5 7 6032.58 5.00 30.4

TABLE 22 Prototype 6 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 51594.40 0.50 26.0 2 37405.94 1.00 37.7 332808.75 1.50 49.6 4 29617.17 2.00 59.7 5 27543.47 2.50 69.4 6 26359.453.00 79.7 7 26511.58 2.50 66.8 8 27285.50 2.00 55.0 9 28575.36 1.50 43.210 31452.74 1.00 31.7 11 38497.36 0.50 19.4

TABLE 23 Prototype 8 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 10021.22 1.00 10.1 2 5671.65 7.33 41.9 34833.98 13.67 66.6 4 4365.68 20.00 88.0 5 4536.39 13.67 62.5 6 5048.987.33 37.3 7 7441.50 1.00 7.5

TABLE 24 Prototype 9 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 16272.08 1.00 16.4 2 6335.91 7.00 44.7 34327.52 13.00 56.7 4 3806.91 19.00 72.9 5 3278.23 25.00 82.6 6 3655.4719.00 70.0 7 3900.11 13.00 51.1 8 5442.93 7.00 38.4 9 22126.06 1.00 22.3

TABLE 25 Prototype 10 speed ramp rheology results. Step Viscosity (cP)Speed (rpm) Torque (%) 1 5873.82 5.00 29.6 2 756.16 23.75 18.1 3 431.9042.50 18.5 4 239.75 61.25 14.8 5 182.32 80.00 14.7 6 226.79 61.25 14.0 7410.89 42.50 17.6 8 994.29 23.75 23.8 9 4722.87 5.00 23.8Summary

Following collation and examination of the results above, prototypeformulations 2, 3, 6, 7 and 10 was selected for progression to the nextround of development. This decision was reached on review of the earlydissolution results and also the ease of handling during mixing,degassing and filling.

Additionally, it was attempted to keep the scope of gelling agents aswide as possible within this reduced number of lead prototypes. For thisreason, prototype 6 was included as it allowed the inclusion of theviscosity modifier Xantural 75 (which was not present in prototypes2,3,7 or 10) in the next round of optimisation. Selecting Prototype 9,which had a more favourable dissolution profile at this stage, wouldhave used Kelcogel which was already present in Prototype 3 and had beenselected for progression. It was anticipated that there was scope forreducing the concentration of viscosity modifer in Prototype 6 in orderto obtain the desired release profile, whilst still maintaining a highvisocosity and abuse deterrent characteristics.

It is recommended that the ratios of excipients in prototype 7 beadjusted to lower the percentage of viscosity modifier (CMC 7H3 SF) inthe formulation. Although the release of this prototype was not asfavourable as some of the others, the very high viscosity suggests thatthere is scope for reduce the concentration of CMC 7H3 SF, which wouldalso be expected to result in a more favourable dissolution profile.

Example 2: Prototypes 2, 3, 6, 7, and 10

This example demonstrates the optimization and testing of five leadprototypes 2, 3, 6, 7, and 10.

Prototypes 2, 3, 6, 7 and 10 were prepared on a larger scale (100 g, 50g, and 30 g) to allow a better appreciation of how the formulationhandles and fills. These prototype formulations have been subject todissolution testing and extraction in 3 mL 40% EtOH (to simulatepreparation in a small volume for injection) and an initial assessmentof solvent extractability (related to abuse deterrent behaviour). Theresults of these assessments were then used to optimise the formulationsby adjusting ratios of excipients and/or substituting excipients toachieve the desired dissolution and abuse deterrence profiles.

From the results of these tests, a lead round from each prototype wasthen subject to a short stage of abuse deterrence testing. Based on theresults of these tests, along with observations of the formulations andtheir handle-ability/process-ability, Prototype 2 (round 3), Prototype 3(round 1) and Prototype 7 (round 1) have demonstrated superiordissolution and ADF characteristics.

Prototypes, 6 and 10 were excluded from further development at thisstage. Prototype 6 failed to achieve complete dissolution within 45 minin any round of development, and the lead (Round 3) was significantlysyringe-able/extractable in ambient water. Improving dissolution in thisformulation would likely result in loss of remaining ADF characteristicsunless extensive reformulation was carried out. Despite promisingdissolution, Prototype 10 proved challenging to handle. It was observedto separate upon standing and the most favourable (Round 3) wasextensively syringe-able/extractable in hot and ambient water. Attemptsto improve handle-ability by reducing content of viscosity modifier towould likely result in increased extraction potential.

Materials & Equipment

Raw Materials

The raw material (RRM) number, manufacturer's batch number, manufacturerand expiry date for the materials used in these studies are detailed inTable 28.

TABLE 26 Batch details for excipients and drug substance used duringthis study. Material Function Manufacturer Kollisolv P124 Carrier BASFKolliphor EL Carrier BASF Gelucire 48/16 Carrier Gattefosse Superrefined Corn Oil Carrier Croda Xantural 75 Viscosity modifier KelcoKelcogel CGHA Viscosity modifier Kelco CMC 7H3SF Viscosity modifierASHLAND Methocel A4CP Viscosity modifier Dow Gelatin Type B 220 BloomBanding solution Gelita component Sterile water for Irrigation Bandingsolution Flowfusor component Absolute ethanol Banding solution Fishercomponent Pharmacoat 603 Banding solution Shin-Etsu component Size 0Conisnap white/white Capsule shell Capsugel (gelatin) Size 0 VCaps PlusCapsule shell Capsugel white/white (HPMC) Ethanol absolute (Emprove)Extraction solvent Merck MilliQ water Extraction solvent Filteredin-house on day of use Dextroamphetamine Sulfate API CambrexMethods

Preparation of Bulk Mixes

Three rounds of prototypes 2, 3, 6, 7 and 10 were prepared during theoptimisation phase. See Table 27 for excipient ratios for each round ofoptimisation. The excipients were dispensed into labelled amber glassjars and high shear mixed until visually homogenous. The temperaturebefore and after high shear mixing was recorded for each formulation,along with mixing time. The Gelucire 48/16 was dispensed as a solid atroom temperature (pelletised) and allowed to melt in an oven at 60° C.before mixing. Once homogenous, the mixes were degassed in a vacuumchamber prior to filling into capsules.

TABLE 27 Excipient ratios used in rounds 1, 2 and 3 for the fiveprototypes. Excipient Round 1 Round 2 Round 3 Prototype 2 Kollisolv P12470 65 40 Kelcogel CGHA 30 35 30 Gelucire 48/16 N/A N/A 30 Prototype 3Gelucire 48/16 70 75 55 Kelcogel CGHA 30 25 25 Miglyol 812N N/A N/A 20Prototype 6 Kolliphor EL 60 50 50 Xantural 75 40 30 15 Miglyol 812N N/A20 35 Prototype 7 Kolliphor EL 70 50 40 CMC 7H3SF 30 30 30 Miglyol 812NN/A 20 30 Prototype 10 Corn oil 51 18 47.5 Kolliphor EL 22 N/A N/AKolliphor RH40 N/A 60 29 Methocel A4CP 27 22 22 Aerosil 200 N/A N/A 1.5

Capsule Filling and Banding

Bulk mixes were filled into capsule shells at a target fill weight of550 mg (±7.5%) with a target dose of 30 mg dextroamphetamine sulfate.Round 1 formulations were prepared at 100 g scale and filled using theHibar semi-automatic capsule filling machine. The round 1 formulationswere filled half into gelatin and half into HPMC capsules.

Formulations from rounds two and three were filled exclusively intogelatin capsule shells. Round 2 formulations were prepared at 30 g scaleand round 3 formulations at 50 g scale. Round 2 and 3 formulations werefilled into capsules by hand, using a syringe body with no needle.Initially a third Round of prototype 2 was not carried out, however thiswas performed later following review of available data.

Multiple gelatin banding solutions and HPMC banding solutions were usedduring this study, prepared as per SOP-MAN-0513. These were used toapply a band to the cap/body join of the filled capsules using abenchtop Qualiseal banding machine and left to cure overnight. Followingband drying, capsules were spread onto witness paper and subject tovacuum testing for 20 min at <−7.4 “Hg. Any capsules found to leak wereremoved from the batch. In all cases of leaking, this was a result of aflaw in the banding resulting from formulation contamination on theoutside of the capsule body during hand-filling, and was not a functionof the formulation itself.

Dissolution

Dissolution was carried out on all prototype formulations from eachround, using USP Apparatus III dissolution bath (n=6). The dissolutionconditions used are outlined in Table 28 and the analytical reagentsused are outlined in Table 29. The mobile phase was prepared bydissolving 1.1 g of Sodium-l-heptanesulfonate in 575 mL of UHQ Water. 25mL of dilute glacial acetic acid (prepared by diluting 14 mL acetic acidin 100 mL UHQ Water) and 400 mL of methanol were added and pH wasadjusted to pH 3.3±0.1 using glacial acetic acid. The API workingstandard was prepared by dissolving 8 mg Dextroamphetamine Sulfate in150 mL of dissolution media and sonicating for 10 min before making upto 250 mL.

TABLE 28 Dissolution conditions Parameter Equipment/Setting Dissolutionapparatus USP apparatus III (EI/415) Filter type 40/35 μm probe filterMedium type 0.01M HCl Medium volume 250 mL Sample times 5, 10, 15, 20,30 and 45 minutes Sample volume 2 mL (filter not replaced) Vesseltemperature 37° C. ± 0.5° C. Dip rate 30 dips per minute Mesh screensize 840 μm

TABLE 29 Reagents used for dissolution Reagent Grade UHQ water UHQAcetic acid glacial ARG grade Methanol HPLC grade Hydrochloric acid ARGSodium-1-HeptaneSulfonate 1-Heptanesulphonic Acid Sodium Salt HPLC gradeDextroamphetamine Sulfate USP

Extraction

A brief extraction assessment was carried out on one capsule from eachbatch. The capsule was crushed using a mortar and pestle then groundwith 2 mL 40% EtOH at room temperature for 5 minutes. The resultantmaterial was transferred into a scintillation vial and a further 1 mL ofsolvent (total 3 mL) was used to rinse the mortar and pestle into thevial. This was shaken at room temperature for 120 minutes an ambientshaking table before being passed through a 0.45 μm syringe filter. Anyfiltrate produced was collected and passed to analytical development forquantification of API by HPLC.

For the sample preparation, 15 mL of diluent was added and shakenthoroughly by hand before filtering through a 0.45 μm syringe filter. 3mL of the resulting filtrate was then made to volume into a 25 mLvolumetric flask with diluent.

For the HPLC analysis, mobile phase A was prepared by dissolving 5 mL ofTrifluoroacetic Acid in 900 mL of water before adjusting to pH of2.2(±0.1) with ammonium hydroxide. Acetonitrile (100 mL) was then addedand mixed. The solution was allowed to equilibrate to room temperaturebefore use. The HPLC conditions are detailed in Table 30 and the HPLCgradient method used is detailed in Table 31. Finally, the reagents usedare detailed in Table 32.

TABLE 30 HPLC conditions used for extraction test ParameterEquipment/Setting Column Phenomenex Prodigy C18 150 mm × 3.0 mm (5 μm)Flow rate 0.7 mL/min Injection volume 20 μL Column temperature 40° C. UVdetection 257 nm Mobile phase A TFA:Water:Acetonitrile 90/0.5/10 v/v/v(pH 2.2) Mobile phase B 100% Acetonitrile Typical retention timeApproximately 6-7 min Run time 30 min

TABLE 31 HPLC gradient for analysis of extraction samples. Time (min) %A % B 0 100 0 15 65 35 20 0 100 22 0 100 23 100 0 30 100 0

TABLE 32 Reagents used for analysis of extraction samples Reagent GradeUHQ water UHQ Trifluoroacetic acid LC/MS Ammonium Hydroxide ARG 35%Acetonitrile HPLC grade Dextroamphetamine Sulfate USP

Short ADF Screen

The ADF screen included evaluating (1) the ability of the prototypes tobe physically manipulated into a form suitable for insufflation, (2) theamount of API chemically extracted, (3) the syringable volume, and (4)the volume of dilution for syringability. The acceptance criteria forthe testing are described in Table 33.

TABLE 33 Acceptance criteria for short ADF screen. Pass Test DescriptionCriteria Physical The percentage passing through the sieve ≤30% ChemicalExtraction The quantity extracted ≤30% Syringeability The quantitysyringe-able/extracted ≤30% Syringeability The volume of dilution forsyringeability >10 mL

Syringeability. For syringeability testing, where the sample could notbe drawn into the syringe using a cotton wool filter, a cigarette filterwas used for the second preparation. If the cigarette filter wasunsuccessful, no filter was used and an attempt was made to draw thesample into the syringe barrel in the absence of a filter or needle,before attaching a needle and attempting to expel the contents into avolumetric flask for analysis. Analysis by HPLC carried out as per theextraction method detailed above.

Physical manipulation. Samples were prepared for insufflation. Capsuleswere frozen in a domestic freezer and then ground in a domestic coffeegrinder before attempting to pass the ground material through a sieve(106 μm) by gravity and weighing the material which passed through.

Capsule Shell Compatibility Assessment with Gelatin and HPMC Shells

Twenty capsules from each of the first round batches were packed intoamber glass jars and sealed with parafilm. These jars were then placedin a stability cabinet (40° C./75% RH) for two weeks. Following therequired storage period, the capsules were removed and examined visuallyfor signs of gross incompatibility.

Results

Preparation of Bulk Mixes, Capsule Filling and Capsule Banding

Details of dispensed quantities for the first round of prototypes areoutlined in Table 34 to Table 38. Following review of the dissolutionand initial extraction data, these were adjusted for second and thirdrounds of preparation (see Table 39 to Table 43 for Round 2; see Table44 to Table 48 for Round 3). The original planned ratio has beendetailed in the first line of each table, with the actual excipientratio included in the last column to account for any adjustments thathad to be made during preparation for handle-ability. Temperatures ofmixes before and after high shearing, where available, are recorded inTable 49.

Following banding and curing, all capsules were subject to a vacuum testto remove any leaking capsules. All leaking capsules were examined, andthe leaks were found to be a result of poor band adherence, due tocontamination of outside of capsule shell with formulation. This iscommon in technical scale manufactures, due to the level of manualhandling required at this scale. All of the round 1 prototypes weresubject to a physical examination and no signs of capsule embrittlementwere present at t=0.

TABLE 34 Dispensed quantities for Prototype 2 Round 1 KollisolvP124:Kelcogel CGHA 70:30 PROTOTYPE 2 ROUND 1 Bulk mix quantity ActualActual theoretical dispensed Balance excipient % (w/w) (g) weight (g) IDratio API 5.4550 5.4550 5.4409 EI/171 Kollisolv P124 66.1815 66.181566.16 EI/77 69.99 Kelcogel 28.3635 28.3635 28.37 EI/77 30.01 CGHA Total100.0000 100.0000

TABLE 35 Dispensed quantities for Prototype 3 Round 1 Gelucire48/16:Kelcogel CGHA 70:30 PROTOTYPE 3 ROUND 1 Bulk mix quantity ActualActual theoretical dispensed Balance excipient % (w/w) (g) weight (g) IDratio API 5.4550 5.4550 5.4438 EI/171 Gelucire 48/16 28.3635 28.363566.14 EI/77 70.00 Kelcogel 66.1815 66.1815 28.35 EI/77 30.00 CGHA Total100.0000 100.0000

TABLE 36 Dispensed quantities for Prototype 6 Round 1 KolliphorEL:Xantural 75 60:40 PROTOTYPE 6 ROUND 1 Bulk mix quantity Actual Actualtheoretical dispensed Balance excipient % (w/w) (g) weight (g) ID ratioAPI 5.4550 5.4550 5.4412 EI/171 Koliphor EL 56.7270 56.7270 56.74 EI/7760.02 Xantural 75 37.8180 37.8180 37.8 EI/77 39.98 Total 100.0000100.0000

TABLE 37 Dispensed quantities for Prototype 7 Round 1 Kolliphor EL:CMC7H3SF 70:30 PROTOYPE 7 ROUND 1 Bulk mix quantity Actual Actualtheoretical dispensed Balance excipient % (w/w) (g) weight (g) ID ratioAPI 5.4550 5.4550 5.4753 EI/171 Kolliphor EL 66.1815 66.1815 66.14 EI/7770.00 CMC 7H3SF 28.3635 28.3635 28.35 EI/77 30.00 Total 100.0000100.0000

TABLE 38 Dispensed quantities for Prototype 10 Round 1 Cornoil:Kolliphor EL:Methocel A4CP (54:23:23) PROTOTYPE 10 ROUND 1 Bulk mixquantity Actual Actual theoretical dispensed Balance excipient % (w/w)(g) weight (g) ID ratio API 5.4550 5.4550 5.4531 EI/171 Corn oil 51.054351.0543 51.05 EI/77 51.27 Kolliphor EL 21.7454 21.7454 21.73 EI/77 21.82Methocel 21.7454 21.7454 26.79 EI/77 26.91 A4CP Total 100.0000 100.0000

TABLE 39 Dispensed quantities for Prototype 2 Round 2 KollisolvP124:Kelcogel CGHA 60:40 PROTOTYPE 2 ROUND 2 Bulk mix quantity ActualActual theoretical dispensed Balance excipient % (w/w) (g) weight (g) IDratio API 5.4550 1.6365 1.6317 EI/171 Kollisolv P124 56.7270 17.018121.0864 EI/7 65.00 Kelcogel 37.8180 11.3454 11.3542 EI/77 35.00 CGHATotal 100.0000 30.0000 Note additional Kollisolv required forhandle-ability.

TABLE 40 Dispensed quantities for Prototype 3 Round 2 Gelucire48/16:Kelcogel CGHA 75:25 PROTOTYPE 3 ROUND 2 Bulk mix quantity ActualActual theoretical dispensed Balance excipient % (w/w) (g) weight (g) IDratio API 5.4550 1.6365 1.63106 EI/234 Gelucire 48/16 70.9088 21.272621.2366 EI/043 74.99 Kelcogel 23.6363 7.0909 7.081 EI/043 25.01 CGHATotal 100.0000 30.0000

TABLE 41 Dispensed quantities for Prototype 6 Round 2 KolliphorEL:Miglyol 812N:Xantural 75 50:20:30 PROTOTYPE 6 ROUND 2 Bulk mixquantity Actual Actual theoretical dispensed Balance excipient % (w/w)(g) weight (g) ID ratio API 5.4550 1.6365 1.6337 EI/171 Koliphor EL47.2725 14.1818 14.1108 EI/7 50.00 Miglyol 812N 18.9090 5.6727 5.6443EI/7 20.00 Xantural 75 28.3635 8.5091 8.4665 EI/7 30.00 Total 100.000030.0000

TABLE 42 Dispensed quantities for Prototype 7 Round 2 KolliphorEL:Migyol812N:CMC 7H3SF 50:20:30 PROTOYPE 7 ROUND 2 Bulk mix quantityActual Actual theoretical dispensed Balance excipient % (w/w) (g) weight(g) ID ratio API 5.4550 1.6365 1.6324 EI/171 Kolliphor EL 47.272514.1818 14.14 EI/7 49.80 Miglyol 812N 18.9090 5.6727 5.7011 EI/7 20.08CMC 7H3SF 28.3635 8.5091 8.5516 EI/7 30.12 Total 100.0000 30.0000

TABLE 43 Dispensed quantities for Prototype 10 Round 2 Cornoil:Kolliphor REMO:Methocel A4CP (20:50:30) PROTOTYPE 10 ROUND 2 Bulkmix quantity Actual Actual theoretical dispensed Balance excipient %(w/w) (g) weight (g) ID ratio API 5.4550 1.6365 2.2216 EI/171 Corn oil18.9090 5.6727 6.74 EI/7 17.48 Kolliphor 47.2725 14.1818 23.29 EI/760.42 RH40 Methocel 28.3635 8.5091 8.52 EI/7 22.10 A4CP Total 100.000030.0000 Note additional Kolliphor RH40 and corn oil required forhandleability.

TABLE 44 Dispensed quantities for Prototype 2 Round 3 KollisolvP124:Kelcogel CGHA:Gelucire 48/16 40:30:30 PROTOTYPE2 ROUND 3 Bulk mixquantity Actual Actual theoretical dispensed Balance excipient % (w/w)(g) weight (g) ID ratio API 5.4550 1.0910 1.0906 EI/171 Kollisolv P12437.8180 7.5636 7.5769 EI/043 40.05 Kelcogel 28.3635 5.6727 5.6722 EI/04329.98 CGHA Gelucire 48/16 28.3635 5.6727 5.6716 EI/043 29.98 Total100.0000 14.3273 Note this was carried out after the other prototypes

TABLE 45 Dispensed quantities for Prototype 3 Round 3 Gelucire48/16:Kelcogel CGHA:Miglyol 50:25:20 PROTOTYPE 3 ROUND 3 Bulk mixquantity Actual Actual theoretical dispensed Balance excipient % (w/w)(g) weight (g) ID ratio API 5.4550 2.7275 2.7195 EI/171 Gelucire 48/1651.9998 25.9999 25.99 EI/7 55.02 Kelcogel 23.6363 11.8181 11.8 EI/724.98 CGHA Miglyol 812N 18.9090 9.4545 9.45 EI/7 20.00 Total 100.000050.0000

TABLE 46 Dispensed quantities for Prototype 6 Round 3 KolliphorEL:Miglyol 812N:Xantural 75 50:35:15 PROTOTYPE 6 ROUND 3 Bulk mixquantity Actual Actual theoretical dispensed Balance excipient % (w/w)(g) weight (g) ID ratio API 5.4550 2.7275 2.72 EI/171 Koliphor EL47.2725 23.6363 23.63 EI/7 50.02 Miglyol 812N 33.0908 16.5454 16.53 EI/734.99 Xantural 75 14.1818 7.0909 7.08 EI/7 14.99 Total 100.0000 50.0001

TABLE 47 Dispensed quantities for Prototype 7 Round 3 KolliphorEL:Migyol812N:CMC 7H3SF 40:30:30 PROTOYPE 7 ROUND 3 Bulk mix quantityActual Actual theoretical dispensed Balance excipient % (w/w) (g) weight(g) ID ratio API 5.4550 2.7275 2.724 EI/171 Kolliphor EL 37.8180 18.909018.89 EI/7 39.99 Miglyol 812N 28.3635 14.1818 14.17 EI/7 30.00 CMC 7H3SF28.3635 14.1818 14.13 EI/7 29.91 Total 100.0000 50.0000

TABLE 48 Dispensed quantities for Prototype 10 Round 3 Cornoil:Kolliphor RH40:Methocel A4CP:Aerosil 30:40:28:2 PROTOTYPE 10 ROUND 3Bulk mix quantity Actual Actual theoretical dispensed Balance excipient% (w/w) (g) weight (g) ID ratio API 5.4550 2.7275 2.7158 EI/171 Corn oil28.3635 14.1818 30.73 EI/7 47.49 Kolliphor 37.8180 18.9090 18.91 EI/729.22 RH40 Methocel 26.4726 13.2363 14.12 EI/7 21.82 A4CP Aerosil 2001.8909 0.9455 0.95 EI/7 1.47 Total 100.0000 50.0000 Note additional cornoil added for handle-ability. Nominal dose of this batch adjusted to22.15 mg and results of analyzes corrected accordingly.

TABLE 49 Temperatures before and after high shear mixing, and durationof high shear, where recorded. Temp prior Temp Duration to highfollowing of high shear high shear shear (° C.) (° C.) (min) Prototype 2Round 1 20.6 38.5 4 Round 2 23.6 29.4 3 Round 3 42.4 30.4 not recordedPrototype 3 Round 1 not recorded not recorded 4 Round 2 55.5 46.4 1.5Round 3 not recorded not recorded 2 Prototype 6 Round 1 21.8 34.6 7Round 2 21.7 40.1 3 Round 3 not recorded not recorded 2 Prototype 7Round 1 21.6 42.6 3.5 Round 2 23.7 36   3 Round 3 not recorded notrecorded 2 Prototype 10 Round 1 21.6 31.7 5 Round 2 ~50   47.3 4 Round 320.1 18.9 2

Capsule Shell Compatibility Assessment with Gelatin and HPMC Shells

Following storage for two weeks in glass jars at 40° C./75% RH, thegelatin and HPMC capsules from Round 1 were removed and examined forsigns of gross incompatibility. One minor leak was observed in Prototype6 (gelatin), however on examination this was found to be from a bubblein the gelatin band, rather than any incompatibility. All other capsuleswere viable and there were no signs of incompatibility in either gelatinor HPMC. This assessment was included at this stage as brittle capsuleshad been found at the early capsule shell compatibility study. At thetime of that investigation, it was anticipated that this was a result ofa gross humidity deviation in the development laboratory during banddrying. Results of the latest study confirm that there are no signs ofincompatibility between these formulations and either gelatin or HPMCshells.

Optimisation Testing Results and Discussion

Dissolution

Dissolution profiles were obtained using a USP Apparatus III dissolutionbath and are shown in FIGS. 1 to 5 . The equivalent dissolution profilefor the comparator (Barr 10 mg IR tablet) has been included forinformation. In order to obtain an appropriate dose, three tablets wereplaced in a gelatin shell (unbanded) to represent one 30 mg dosage form.

For Prototype 2, all rounds achieved complete release within 45 min,with a more gradual release profile for the third round, following theaddition of Gelucire 48/16, a thermosoftening excipient which produced aplug which eroded more slowly in the dissolution bath, shown in FIG. 1 .

For Prototype 3, there was not a significant difference between thedissolution profiles from the first to second rounds, following a slightreduction in Kelcogel content (92.9% release cf 91.5%, FIG. 2 ).Substitution of a portion of the Gelucire 48/16 carrier excipient forMiglyol 812 resulted in a slight reduction in release (83.9%).

For Prototype 6, the third round of dissolution was most favourable,with 86.2% release after 45 min, compared to 56.8% and 56.2% in theearlier rounds, see FIG. 3 . More favourable dissolution was achieved bylowering the content of Xantural (xanthan gum) for Migylol 812N (amedium chain triglyceride), however dissolution at 45 min was stillsignificantly less than the comparator, under these conditions, andfurther formulation optimisation would be required on this prototype.

For prototype 7, only 79.5% 82.6% and 74.4% release were achieved in 45min for Rounds 1, 2 and 3, respectively, see FIG. 4 .

Finally, an adjustment of Prototype 10 provided an improvement indissolution from 90.4% in Round 1 to 105.5% in Round 2 and 102.5% inRound 3 (FIG. 5 ). In the second round this was achieved by reducing thecontent of corn oil from (a long chain triglyceride) and Methocel, andsubstituting Kolliphor EL for Kolliphor RH40 at a greater percentage(see Table 27 for details). In the third round, Aerosil 200 was added inan attempt to prevent sedimentation in the formulation but this resultedin handling issues and additional corn oil was added during processing.A suitable formulation viscosity was not achieved whilst maintaining astable suspension for this prototype and further development would berequired.

Extraction

In order to assess abuse deterrence potential, a small volume extractionwas performed in 40% ethanol. Complete extraction was not obtained in 3mL 40% EtOH for any of the prototypes. On manipulation, prototypes 6, 7and 10 produced very viscous gels which were challenging to handle.Prototype 6 rapidly blocked the syringe filter and no filtrate wasobtained in any round. A small amount of cloudy filtrate was obtainedfor Prototype 10 for rounds 1 and 2. In round 2, prototype 7 appeared toproduce a small amount of filtrate, however a significant amount of APIwas not recovered. In round 3 only prototype 3 produced a filtrate.

Table 50 summarizes the extraction data, which is also presented in thebar graph of FIG. 6 . In general, prototypes 6, 7 and 10 demonstratedsuperior best performance in this test in all Rounds.

TABLE 50 Initial extraction data for Prototypes 2, 3, 6, 7 and 10 ingelatin shells (n = 1). % Recovered based on Label Content PrototypeRound 1 Round 2 Round 3 2 12.4  13.8  ND 3 1.3 8.6 6.7 6 ND ND ND 7 ND0.2 ND 10 0.2 0.1 ND

The extraction test was then repeated for Prototype 3 Round 1 andPrototype 7 Round 1 with a greater number of repeats (n=3), in order toassess the reliability of the original assessments prior to selectionfor full ADF screening. The extraction results of the repeated tests aresummarized in Table 51. The repeat analyzes were consistent with theoriginal n=1 data.

TABLE 51 Repeat extraction test on Prototype 3 and 7 Round 1 in gelatinshells (n = 3) % Recovered based on Label Content Prototype 1 2 3Average Prototype 3 Round 1 0.6 2.3 7.0 3.3 Prototype 7 Round 1 ND ND NDND

Short ADF Screen

A brief set of abuse deterrence tests were carried out on the leadformulation from each prototype to give an indication of potential ADFperformance. The lead formulations tested at this stage were Prototype 2Round 2, Prototype 3 Round 2, Prototype 6 Round 3, Prototype 7 round 3and Prototype 10 Round 3. All prototypes passed the physicalmanipulation test (an indication of ease of preparation forinsufflation), with less than 30% of mass passing through the sieve,suggesting an inherent resistance against preparation for insufflationwith these formulations due to the liquid or semisolid nature.

A summary of the extractability/syringeability in 10 mL water isprovided in Table 53. Following these results, it was decided to carryout the short ADF testing on Prototype 2 round 3, Prototype 3 round 1and Prototype 7 Round 1, to determine if these rounds had morefavourable ADF characteristics.

For the extractability/syringeability there was no measurable recoveryfrom Prototype 2 Round 2 in ambient water (n=2), however 13.2 mg (44%)and 5.7 mg (19%) were recovered from the hot water preparations (Table52). Moving to the third round prototype, this improved to 0.33 mg(1.1%), 0.25 mg (0.8%) and no recovery for cotton wool, cigarette filterand no filter, respectively in hot water (Table 53). The third roundformulation also showed superior resistance in the 40% EtOH extractiontest, c.f. rounds 1 and 2 (see section 3.3.2).

For prototype 3 round 2, there was no recovery from one ambient watersample, and 1.2 mg recovery from the other. For the hot water samples,3.7 mg and 5.8 mg were recovered (Table 52). Moving to the First Roundfor Prototype 3, there was no measurable recovery of API from any of therepeats in the syringeability/extraction testing (Table 53). FIG. 7shows an image of the sample following the shaking period. Thisindicates favourable AD behaviour in Prototype 3 Round 1. The firstround formulation also showed superior resistance in the 40% EtOHextraction test, c.f. rounds 1 and 2 (see section 3.3.2).

Results for Prototype 7 were inconsistent, with one hot water sampleproducing no measureable extraction, and the other hot water sampleresulting in recovery of 13.8 mg. This may have been a result ofinhomogeneity due to separation of the formulation. There was nomeasureable extraction in either of the cold water samples for thisprototypes. Following this and review of dissolution data, it wasdecided to perform a short ADF of the first round prototype forPrototype 7. For this prototype, there was no recovery of API fromambient water preparations (n=3) and for hot water preparations, 0.5%,0.5% and 0% of API was recovered for cotton filter, cigarette filter andno filter, respectively. This indicated good AD performance of Prototype7 Round 1.

Prototype 10 Round 3 showed some extraction in both hot and cold water,and therefore the least AD potential in these tests.

Whilst there was no measurable extraction in the hot water preparationsfor Prototype 6, 15.1 mg API and 9.2 mg API were recovered in ambientwater preparations making this less favourable as an AD formulation.

TABLE 52 Results of initial short ADF screening.Syringeability/extraction carried out using 26 gauge needle and cottonwool filter. Physical Hot Water Hot Water Ambient Ambient Sample testPrep 1 Prep 2 water Prep 1 water Prep 2 Prototype 2 Pass 6 mL syringed2.5 mL syringed Not Syringeable Not Syringeable Round 2 API = 13.2 mgAPI = 5.7 mg Prototype 3 Pass 1 mL syringed 2 mL syringed NotSyringeable 0.5 mL syringed Round 2 API = 3.7 mg API = 5.8 mg API = 1.2mg Prototype 6 Pass Not Syringeable Not Syringeable 8 mL syringed 6 mLsyringed Round 3 API = 15.1 mg API = 9.2 mg Prototype 7 Pass 2 mLsyringed Not Syringeable Not Syringeable Not Syringeable Round 3 API =13.8 mg Prototype 10 Pass 6 mL syringed 2 mL syringed 5 mL syringed 6 mLsyringed Round 3 API = 7.6 mg API = 1.6 mg API = 7.2 mg API = 15.0 mg

TABLE 53 Further syringeability/extraction investigation results alongwith conditions under which sample was drawn into the syringe barrel Hotwater Ambient Water 1 2 3 1 2 3 Prototype 2 0.33 mg (1.1%) N/A 0.25 mg(0.8%) Not Syringeable Not Syringeable Small amount Round 3 (cotton wool(cotton wool (cotton wool (cotton wool (cigarette drawn into filter)filter) filter) filter) filter) syringe. No sample expelled throughneedle to volumetric for testing (without needle or filter) Prototype 3Not Syringeable Not Syringeable Small amount drawn Not Syringeable NotSyringeable Not Syringeable Round 1 (cotton wool (cigarette into syringe(cotton wool (cigarette (without needle filter) filter) insufficientexpelled filter) filter) or filter) to volumetric for testing (withoutneedle or filter) Prototype 7 Not Syringeable Not Syringeable Smallamount drawn 0.14 mg (0.5%) 0.14 mg (0.5%) Drug syringed Round 1 (cottonwool (cigarette into syringe drug syringed drug syringed but no recoveryfilter) filter) insufficient expelled (cotton wool (cotton wool by HPLCto volumetric for filter) filter) (without needle testing or filter)(without needle or filter)

Summary of Results and Discussion

TABLE 54 Observations and comments from preparation of bulk mixes,capsule filling and subsequent testing. Prototype Number Summary ofResults and Observations Prototype 2 Round 1 Mixed and degassed easilyat room temperature. Formulation tailed on filling, alleviated with useof bottom function. Favourable dissolution but most extractable out offive prototypes in this round. Rapid dissolution. Round 2 Kelcogelcontent was increased in this round to attempt to improveextractability. 60:40 formulation was too viscous to allow processingand so additional Kollisolv was added (65:35 resulted). Remainedchallenging to process due to viscosity. Some syringeability in hotwater observed in short ADF screen. Round 3 Gelucire 48/16 added.Handled well at elevated temperature (40-60° C.). No filtrate could beproduced for 40% EtOH extraction. Minimal extraction/syringeability inhot water. No measureable extraction/syringeability in ambient water.Favourable dissolution. Prototype 3 Round 1 Thermosoftening formulation.Filled with hopper and pump block at 55° C. Some tailing but possible tofill without bottom function. Slow dissolution. Promisingsyringeability/extractability performance in short ADF screen in allconditions Round 2 Reduced quantity of Kelcogel, but this did notsignificantly change dissolution. Mixed, degassed and filled easily.More extractable than Round 1. Round 3 Mixed, degassed and filledeasily. Dissolution slower than Round 1 or 2. Improvement inextractability c.f Round 2 but less favourable than round 1. Prototype 6Round 1 Mixed easily. Degassing challenging due to proliferation ofbubbles (result of surfactant content). Tailed badly even with bottomon. <60% dissolution achieved. No extraction achieved with 40% EtOHextraction. Reduce viscosity and improve dissolution by reducingXantural content in next round and/or addition of miglyol. Round 2Miglyol added for improved process-ability. Mixed, degassed and filledeasily. Dissolution remained poor. No extraction achieved with 40% EtOHextraction. Round 3 Xantural content decreased and Miglyol contentincreased. Mixed, degassed and filled easily. No extraction achievedwith 40% EtOH extraction. Improved dissolution on third round, but stillonly achieved ~80% release. Whilst this may be improved further with afurther reduction in Xantural 75, this formulation was the mostsyringe-able in short ADF testing, with syringe-ablity/extractability inambient water. Addition of a modifier which gels or swells in ambientwater may improve this formulation.  7 Round 1 Mixed easily. Degassingchallenging due to proliferation of bubbles (result of surfactantcontent). Bottom function required to prevent tailing. Only ~80%dissolution achieved. No API recovery for 40% EtOH extraction (n = 3).Minimal recovery from ambient water syringeability/extraction, nodetectable recovery from hot water preparations. Round 2 Miglyol addedin an attempt to improve dissolution. Mixed, degassed and filled easily.Minimal recovery from 40% EtOH extraction. No improvement indissolution. Round 3 Further miglyol added. Mixed, degassed and filledeasily. Dissolution remains poor. Minimal recovery from 40% EtOHextraction. Some separation observed in formulation. Not syringe-able inhot water but inconsistent syringeability observed in ambient water, mayhave been due to splitting and inhomogeneity. 10 Round 1 Mixed easily.Grainy texture obtained c.f. other formulations. Additional Methoceladded prior to filling as mixture was separating upon standing. Filledwithout bottom function but formulation incorporated air easily and hadto be manually fed towards pump in hopper. Separation may be likely.Round 2 Switched to Kolliphor RH40 to prevent separation and improvehandling. A placebo mix was prepared with corn oil:KolliphorRH40:Methocel (30:40:30) however this was too viscous to allow forprocessing and so 20:50:30 was investigated. Substituted Kolliphor ELfor Kolliphor RH40 for improved handling. 20:50:30 trialed but viscositytoo high, likely due to concentration of methocel. Further RH40 andMiglyol added during bulk mix preparation. Dissolution improved.Additional API added to maintain dose. May be prone to separating.Dissolution improved c.f round 2. Round 3 Aerosil added to preventseparation. Very challenging to process at 30:40:28:2 so more corn oilwas added to improve handleability. No significant change on dissolutionprofile but remained challenging to fill by syringe and most extractablein short ADF testing. Some extraction in all conditions.

Example 3: Comparison of Prototype 2 and a Non-Abuse Deterrent Tablet

This example compares abuse-deterrent formulation Prototype 2 toreference product Barr's 10 mg Dextroamphetamine sulfate tablet andevaluates the relative susceptibility to manipulation or abuse. Barriersto crushing, extraction, and syringeability were evaluated. The testswere based on the methods and protocols described in Appendix A and B.

Physical Barriers to Abuse by Crushing, Cutting or Grinding

Prototype 2 contains the following components per capsule: 10 mg ofdextroamphetamine sulfate; 70 mg of poloxamer 124; 52.5 mg of Gelucire48/16; and 52.5 mg of Kelcogel GCHA for a total fill weight of 185 mg. Asize 3 gelatin capsule was used.

Following grinding of prototype 2 capsule contents, it was observed thatvery little of the material passed through the top sieve (1 mm). Therewas no change in this result following the addition of flux enhancerssuch as talc and sodium chloride. As such, this demonstrated thatprototype 2 was able to prevent abuse via insufflation, which is a knownroute of abuse of amphetamines. In comparison, the ground comparatortablet was collected on all the sieve layers. This shows that thecomparator tablet has the potential to be abused by insufflation.

Prototype 2 capsules and the comparator tablets were subjected tofurther physical testing by grinding with 95% ethanol and evaporatingthe ethanol. Both the capsule and the tablet performed equally well inthis test as the resultant mixture for both was non-powder like andtherefore insufflation assessments could not be performed on either.

Barriers to Abuse Involving Chemical Extraction

Various solvents were used to assess the chemical extraction ofprototype 2 and the comparator tablet. Phase 1 testing was performedusing water, 8% acetic acid, 0.2% sodium bicarbonate, 95% ethanol and acarbonated soft drink. At ambient temperature using 10 mL solvent,greater than 90% of the API was detected in samples after 5 minutes forboth prototype 2 and the comparator tablets. The only exception to thiswas the extraction into water, for which the samples could not befiltered for both formulations.

The effect of 10 mL of hot water was also assessed. For prototype 2, nosamples were analyzed as they could not be filtered. However for thecomparator tablets, full extraction was obtained after 5 minutes. Thisdemonstrates that prototype 2 would not be subject to abuse if hot waterwas used as a means of extraction.

Further chemical extraction assessment was performed using ambient 10 mL40% ethanol. For prototype 2, between 66-81% API was assayed in samplesover the course of the experiment (180 min). However, full extractionwas obtained for the comparator tablets after 5 minutes. These resultsshow that the amount of the API extracted for prototype 2 is less thanthe amount extracted for the comparator tablet and has an extendedextraction time.

Phase 1 Studies

Syringeability Barriers

Phase 1 syringeability assessments were performed using 26 gaugeneedles, which are commonly used by abusers. For prototype 2, thetemperature of the water did not appear to effect the syringeability ofthe sample and for both ambient and hot water, the amount of API assayedwas below 10%. For the comparator tablets, the temperature of the waterresulted in a 20% difference in the API assayed as a greater amount wasobtained following the use of ambient water (66%) compared with hotwater (46%). This demonstrates that prototype 2 is much less susceptibleto abuse via injection in comparison to the comparator tablets.

Phase 2 Studies

Syringeability in Different Gauge Needles After Preparation with Water

In Phase 2 investigations, the effect of different needle gauges wasassessed as well as the effect of different filtration materials (0.2 μmfilter, cotton wool and cigarette filter). Using ambient water and an 18gauge needle, the assayed API results for the prototype 2 samples weremuch lower than the comparator tablets (17% API for needle alone samplesfor prototype 2 and 52% API for needle alone samples for the comparatortablets). In general, these were reduced by the introduction of a filterexcept for filtration through the cigarette filter for the comparatortablet samples.

For samples prepared in hot water, the amount of API present in thesamples for the comparator tablets and prototype 2 were similar when an18 gauge needle was used alone (52% for the comparator and 46% for theprototype 2). Filtration of the prototype 2 samples through cotton wooland cigarette filter reduced the amount of API present in the samples.Filtration of comparator tablet samples reduced the API present when a0.2 μm filter and cotton wool was used but again the cigarette filterhad no effect.

The recovery of API in both ambient and hot water was comparable forprototype 2 and comparator tablet samples when taken up through a 20gauge needle. The prototype 2 samples were subjected to filtrationthrough cotton wool only, which reduced the recovery of API. Filtrationof the comparator samples through a 0.2 μm filter and cotton woolresulted in reductions in the recovery of API. However, as observedpreviously, no reductions in the recovery of API was observed followingfiltration of comparator tablet samples through cigarette filters.

The recovery of API in samples prepared with ambient water and taken upusing a 23 gauge needle was greater in the comparator tablet samplescompared with the prototype 2 samples. Filtration of samples was onlyperformed using the comparator tablet samples. A reduction in therecovery of the API was observed for all filters used (0.2 μm filter,cotton wool and cigarette filter), with the greatest reduction whencotton wool was used. Samples prepared in hot water showed a similaroverall trend to those prepared in ambient water. However for thefiltration step of the comparator tablet samples, the greatest reductionin recovery was observed when a 0.2 μm filter was used.

It should be noted that the use of wider bore needles such as 18, 20 and23 gauge needles is unlikely in an abuse situation as the needle is amuch wider bore and 26 gauge needles would be used preferential as theyare narrower for injection into the vein and more readily available inneedle exchange programmes. In addition, the use of filters only reducesthe amount of the amphetamine available for abuse as opposed to“cleaning up” the solution for injection. In all cases, the recovery ofthe API in prototype 2 was much less compared with the comparatordemonstrating that abuse via injection would be more challenging andwould result in low yields of the drug in compared with the comparatortablets.

Application of Heat—Melting Temperature

Heat was applied to a crushed prototype 2 capsule or comparator tabletand if the contents melted, the ability to syringe the mixture throughvarious gauge needles was assessed. The comparator tablet was heated to200° C. with no changes observed to the powder.

Following the application of heat, the content of prototype 2 melted andwas tested in various gauge needles. It was noted that when the drugproduct was removed from the heat and taken up into the syringe, itsolidified. An 18 gauge and 26 gauge needle was tested and in bothcases, the melted prototype 2 formulation was drawn up but did not reachthe syringe as it solidified.

Although it was possible to melt the prototype 2 formulation, it wouldbe unlikely to be susceptible to abuse as it solidified when taken up inthe needle and would therefore not be suitable for injecting.

Syringeability After Preparation in Water and Multi-Pass Filtering

Following the grinding of either prototype 2 capsules or comparatortablets and testing for syringeability and repeat filtering through acigarette filter, no samples were deemed suitable for analysis from theprototype 2 samples. Comparator tablet samples were analyzed and 38%recovery was observed.

As previously observed, this demonstrates that prototype 2 is notsuitable for abuse via syringing when passed through filters due to thelosses of volume on each pass. In contrast, some API was availablefollowing the same procedure using the comparator tablets.

Syringeability in Different Gauge Needles After Preparation with Ambientand Hot Water

The syringeability of prototype 2 and comparator tablet samples wascompared following preparation in 5 mL ambient and hot water. For allgauge needles tested, the recovery of API in the comparator tabletsamples was greater than in the prototype 2 samples.

The more commonly used 26 gauge needles demonstrated that prototype 2would be much less susceptible to abuse via injection due to the lowyields of drug and the difficultly in syringing the formulation. Thecomparator tablets showed higher yields of the drug and the data for the26 gauge needle was comparable to the wider bore needles when used withprototype 2 in ambient water.

Extraction in Small Volumes of 0.2% Sodium Bicarbonate Solution

The extraction of the API following grinding of the prototype 2 capsuleand comparator tablets was assessed using 5 mL and 2 mL of ambient andhot 0.2% sodium bicarbonate.

Using ambient 0.2% sodium bicarbonate, the recovery was higher in thecomparator tablet samples compared with prototype 2 samples. Forprototype 2 samples prepared using 2 mL of ambient 0.2% sodiumbicarbonate, the sample was not suitable for analysis.

Extraction of samples into hot 0.2% sodium bicarbonate, resulted in fullextraction for the comparator tablet samples. The prototype 2 sampleswere not suitable for analysis.

These results demonstrate the difficulty in extracting the drug forprototype 2 making this an unsuitable route for abuse. Whereas, thecomparator tablet was readily extracted in both volumes of sodiumbicarbonate regardless of temperature.

Ethanol Extraction Test

Prototype 2 and comparator tablet samples were ground with 10 mL 95%ethanol. The resultant mixture was heated to evaporate the ethanol andthe resulting residue was examined. For both formulations, the sampleswere non-powder like and could not be subjected to physical testing toassess the potential for insufflation.

This demonstrates that prototype 2 could not be converted into a powderform. This would prevent abuse via insufflation.

Physical Barriers to Abuse by Crushing, Cutting or Grinding

A common type of misuse of oral pharmaceuticals is abuse by snorting:where an abuser inhales a powdered dosage unit (insufflation).

Phase I Studies

Establish Requirement for Thermal Pre-Treatment

The shell of a whole dose unit was removed and the capsule contents wasplaced into a coffee grinder and ground for five minutes. The resultingproduct was milled to greater than 1 mm. Therefore for all consequentanalyzes, thermal pre-treatment was performed by freezing the capsulesfor 24 hours prior to use.

Milling with a Coffee Grinder

The shells of five whole dosage units (which had been frozen for 24hours) were removed and the capsule contents transferred into a vial andweighed. The capsule contents were placed into a coffee grinder andground for one minute (it should be noted that the comparator tabletcould have been ground further, however in order to provide a suitablecomparison, it was ground for the same amount of time as the prototype 2capsules). The coffee grinder containing the capsule contents wasweighed and then the contents transferred to a 1 mm sieve at the top ofan array. The grinder was re-weighed to confirm the amount of capsulecontents that had been transferred to the sieve array. The particle sizedistribution was determined using 1, 0.5, 0.25 and 0.106 mm pore sizesieves.

The amount of API retained on each sieve was analyzed by HPLC, todetermine if there is any API/excipient segregation during physicalmanipulation.

TABLE 55 Physical testing of Prototype 2 Formulation Sample 1 WeightWeight Weight % of Sieve after before present recovered level (g) (g)(mg) weight 1 mm 218.27126 217.48313 788.13 99.12 0.5 mm 208.12782208.12711 0.71 0.09 0.25 mm 201.92086 201.91843 2.43 0.31 0.106 mm197.23675 197.23555 1.20 0.15 base 128.63762 128.63500 2.62 0.33

TABLE 56 Physical testing of Prototype 2 Formulation Sample 2 WeightWeight Weight % of Sieve after before present recovered level (g) (g)(mg) weight 1 mm 218.39539 217.56326 832.13 100 0.5 mm 209.33688209.33735 −0.47 n/a 0.25 mm 200.84730 200.85005 −2.75 n/a 0.106 mm197.29304 197.29672 −3.68 n/a base 128.07354 128.07638 −2.84 n/a

TABLE 57 Physical testing of Comparator Tablet Formulation Sample 1Weight Weight Weight % of HPLC Sieve after before present recoveredAssay level (g) (g) (mg) weight % API 1 mm 217.98044 217.48976 490.6835.79 96.8 0.5 mm 208.36158 208.13418 227.40 16.59 92.8 0.25 mm202.15150 201.92550 226.00 16.49 68.2 0.106 mm 197.46574 197.24249223.25 16.29 60.6 base 128.83609 128.63267 203.42 14.84 94.6

TABLE 58 Physical testing of Comparator Tablet Formulation Sample 2Weight Weight Weight % of HPLC Sieve after before present recoveredAssay level (g) (g) (mg) weight % API 1 mm 218.11425 217.55891 555.3443.19 95.3 0.5 mm 209.51810 209.33242 185.68 14.44 87.8 0.25 mm201.04832 200.84843 199.89 15.55 65.1 0.106 mm 197.50918 197.29753211.65 16.46 61.0 base 128.20872 128.07554 133.18 10.36 83.6

For prototype 2, the ground capsule contents had clumped together andremained on the 1 mm sieve (see FIG. 9B). Therefore no HPLC assay wasperformed.

For the comparator tablets, both samples showed the greatest amountmaterial retained on the 1 mm layer sieve with similar amounts down tothe 0.106 mm sieve and a decrease on the base (see FIG. 10 ). This maybe due to the comparator tablets being ground for the same amount oftime as the prototype 2 capsules, as a finer powder could have beenachieved if the grinding time had been increased. However, it was deemedthat the same grinding time should be used for both to provide a morecomparable assessment.

Comparator powder from each layer was transferred to 50 ml volumetricflask and made up to volume with the diluent described in the protocol.An HPLC assay was performed on the solutions in the volumetric flasksafter filtering through a 0.45 μm filter. A decrease in the amount ofAPI present as the sieve size decreased until the base where a slightincrease was observed.

Phase II Studies

Phase II studies were performed using all prototype formulations.

Grind with Flux (Flow Enhancers)

The shells of five whole dosage units (which had been frozen for 24hours) were removed. The capsule contents were placed into a mortar andpestle and 0.2 g of a flow enhancer was added, then immediately groundfor five minutes. The particle size distribution was determined using 1,0.5, 0.25 and 0.106 mm pore size sieves, as per Phase I.

TABLE 59 Physical testing of Prototype 2 Formulation Sample 1 using Talcas a Flow Enhancer Weight Weight Weight % of Sieve after before presentrecovered level (g) (g) (mg) weight 1 mm 218.49497 217.49147 1003.5099.29  0.5 mm 208.12175 208.11952 2.23 0.22 0.25 mm 201.91328 201.912790.49 0.05 0.106 mm 197.24210 197.25852 −16.42 n/a base 128.63586128.63140 4.46 0.44

TABLE 60 Physical testing of Prototype 2 Formulation Sample 2 using Talcas a Flow Enhancer Weight Weight Weight % of Sieve after before presentrecovered level (g) (g) (mg) weight 1 mm 218.62971 217.54824 1081.47 1000.5 mm 209.32293 209.32447 −1.54 n/a 0.25 mm 200.83707 200.83836 −1.29n/a 0.106 mm 197.28371 197.28656 −2.85 n/a base 128.07159 128.07228−0.69 n/a

For prototype 2, following grinding with talc, both samples became asticky off white paste (see FIG. 11A). Following visual inspection andweighing of the sieves, the capsule contents was retained on the 1 mmsieve (see FIG. 11B). The data for the weights recovered for the 0.5 mm,0.25 mm and base layers of the sieve array may be attributed to balancevariability as no capsule contents was observed on these layers. As nocapsule contents passed through the 1 mm sieve, no HPLC assay wasperformed.

TABLE 61 Physical testing of Prototype 2 Formulation Sample 1 usingSodium Chloride as a Flow Enhancer Weight Weight Weight % of Sieve afterbefore present recovered level (g) (g) (mg) weight 1 mm 218.49926217.47733 1021.93 99.55 0.5 mm 208.12390 208.12197 1.93 0.19 0.25 mm201.91493 201.91461 0.32 0.03 0.106 mm 197.23175 197.23029 1.46 0.14base 128.63717 128.63624 0.93 0.09

TABLE 62 Physical testing of Prototype 2 Formulation Sample 2 usingSodium Chloride as a Flow Enhancer Weight Weight Weight % of Sieve afterbefore present recovered level (g) (g) (mg) weight 1 mm 218.59888217.55217 1046.7100 100 0.5 mm 209.32548 209.32748 −2.0000 n/a 0.25 mm200.83530 200.83860 −3.3000 n/a 0.106 mm 197.28289 197.28752 −4.6300 n/abase 128.07198 128.07338 −1.4000 n/a

For prototype 2, following grinding with sodium chloride, both samplesbecame a sticky off white paste (see FIG. 12A). Following visualinspection and weighing of the sieves, the capsule contents was retainedon the 1 mm sieve (see FIG. 12B). The data for the weights recovered forthe 0.5 mm, 0.25 mm and base layers of the sieve array may be attributedto balance variability as no capsule contents was observed on theselayers. As no capsule contents passed through the 1 mm sieve, no HPLCassay was performed.

Barriers to Abuse Involving Chemical Extraction

Another common type of abuse is by injection or ingestion. The abuserreduces the unit to particles and extracts or melts the contents of adosage unit in a heated solvent, then swallows or injects the liquid.

Phase I studies were performed using Tier 1 solvents and Phase IIstudies were performed using Tier 2 solvents:

-   -   Tier 1 solvents: Water, Acetic acid (8%), 0.2% Sodium        bicarbonate, Ethanol (95%), Carbonated soft drink (cola, acidic        pH).    -   Tier 2 solvents: Mineral (white) spirits, Ethanol (40%),        Isopropyl alcohol, Methanol, Acetone, 0.1N HC1, 0.1N NaOH.

Phase I Studies

Extraction in Small Volumes of Ambient Tier 1 Solvents

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of a Tier 1 solvent for five minutes or untilhomogeneous. The resulting suspension was transferred to a scintillationvial, the lid covered with Parafilm and shaken in a water bath atambient temperature. Samples were removed at 5, 15, 60 and 180 minutesand filtered through a 0.45 μm filter into a flask and diluted to volumeusing the standard assay method diluent.

The filtered samples were analyzed by HPLC to quantify the API present.

FIGS. 13 and 14 show photographic observations of solvent extraction forPrototype 2 and comparator in Tier 1 solvents.

TABLE 63 Comparison of Solvent Extraction for Prototype 2 (Mean n = 3) %Assay Average Amount Acetic 0.2% Acid Sodium Ethanol Carbonated SampleWater (8%) Bicarbonate (95%) soft drink  5 mins NOT 97 93 113 105 15mins FILTER- 106 92 108 96 60 mins ABLE 105 106 109 102 180 mins  104 95109 98

TABLE 64 Comparison of Solvent Extraction for Comparator TabletFormulation (Mean n = 3) % Assay Average Amount Acetic 0.2% Acid SodiumEthanol Carbonated Sample Water (8%) Bicarbonate (95%) soft drink  5mins NOT 100 102 102 99 15 mins FILTER- 102 105 93 98 60 mins ABLE 101102 94 101 180 mins  101 103 104 103 Note - % Assay calculation based onassumed 10 mg dose

Extraction in Small Volumes of Hot Water

Only hot water was analyzed for this part of the protocol due to theextraction performance of the other prototypes with acetic acid, 0.2%sodium bicarbonate, carbonated soft drink and Ethanol 95%, at ambientconditions.

Water was pre-heated to a proposed extraction temperature of 90° C. asoutlined in protocol.

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of hot water for five minutes until homogeneous. Theresulting suspension was transferred to a scintillation vial, the lidcovered with Parafilm and shaken in a water bath at 90° C. Samples wereremoved at 5, 15, 60 and 180 minutes and, where possible, filteredthrough a 0.45 μm filter into a flask and diluted to volume using thestandard assay method diluent.

The filtered samples were analyzed by HPLC to quantify the API present.FIGS. 15 and 16 show photographic observations of solvent extraction forcomparator and Prototype 2 in hot solvent.

TABLE 65 Comparison of Hot Solvent Extraction into Water (Mean n = 3) %Assay Average Amount Sample Prototype 2 Comparator  5 mins NOTFILTERABLE 103 15 mins 104 60 mins 103 180 mins  106

Phase II Studies

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of 40% ethanol for five minutes until homogeneous. Theresulting suspension was transferred to a scintillation vial, the lidcovered with Parafilm and shaken in a water bath at ambient temperature.Samples were removed at 5, 15, 60 and 180 minutes and filtered through a0.45 μm filter into a flask and diluted to volume using the standardassay method diluent.

The filtered samples were analyzed by HPLC to quantify the API present.FIG. 17 shows photographic observations of solvent extraction forcomparator and prototype 2 in ambient ethanol.

TABLE 66 Comparison of Solvent Extraction for Comparator and Prototype 2in 40% Ethanol (Mean n = 3) % Assay Average Amount Sample Prototype 2Comparator  5 mins 73 104 15 mins 66 102 60 mins 81 104 180 mins  79 101

Syringeability Barriers

Phase I Studies

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of water at ambient temperature for up to thirtyminutes until homogeneous. The solution was drawn into a syringe via a26-gauge needle and the approximate amount of liquid drawn recorded. Incases where 1 mL or greater was drawn up and was fluid enough to beexpelled through the needle, the syringe contents was dispensed intosuitably sized volumetric flasks and prepared for HPLC analysis usingthe standard assay method diluent.

Samples that passed the test criteria at room temperature (<5% yield)were repeated using water heated to 90-95° C. FIGS. 18 and 19 showphotographic observations of the syringability in ambient water and hotwater, respectively, of comparator and Prototype 2 with a 26 gaugeneedle.

TABLE 67 Syringeability in Ambient Water with a 26 Gauge Needle andAssay of Syringed Samples Average Volume Assayed Assayed syringed/drawnconcentration Concentration Formulation Sample (mL) % % Prototype 2 11.0 7.4 4 2 1.0 5.2 3 <0.5 ml 4.9 Comparator 1 6.0 61.6 66 2 6.0 62.0 37.0 73.4

TABLE 68 Syringeability in Hot Water with a 26 Gauge Needle and Assay ofSyringed Samples Average Volume Assayed Assayed syringed/drawnconcentration Concentration Formulation Sample (mL) % % Prototype 2 11.0 9.2 7 2 1.0 7.2 3 1.0 5.1 Comparator 1 4.5 46.8 46 2 5.0 54.1 3 3.536.9

Phase II Studies

Phase II studies were performed using all prototype formulations.

Syringeability in Different Gauge Needles After Preparation with Water

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of water at ambient temperature for five minutes oruntil homogenous. The solution was drawn into a syringe via an 18-gaugeneedle and the approximate amount of liquid drawn recorded. In caseswhere 1 mL or greater was drawn up and was fluid enough to be expelledthrough the needle, the syringe contents was dispensed into suitablysized volumetric flasks and prepared for HPLC analysis using thestandard assay method diluent.

The above process was repeated with attempts to draw the solution via a0.2 μm filter, a wad of cotton wool and a cigarette filter tip. A freshsample was prepared for each filter used.

The above experiment was repeated using a narrower gauge needle forsamples that were syringeable with the 18-gauge needle and progressedvia the 20 and 23-gauge needles as long as the recovered quantity of APIwas greater than 5% of the dose recovered.

Samples that passed the test criteria at room temperature (<5% yield)were repeated using water heated to 90-95° C.

FIGS. 20 and 21 show photographic observations of the syringeability ofcomparator and Prototype 2, respectively, in ambient water with an 18gauge needle with and without a variety of filters. FIGS. 22 and 23 showphotographic observations of the syringeability of comparator andPrototype 2, respectively, in hot water with an 18 gauge needle with andwithout a variety of filters. FIG. 24 shows photographic observations ofthe syringeability of comparator in ambient water with a 20 gauge needlewith and without a filter. FIG. 25 shows photographic observations ofthe syringeability of comparator and Prototype 2 in hot water with a 20gauge needle. FIG. 26 shows photographic observations of thesyringeability of comparator in ambient water with a 23 gauge needlewith and without a filter. FIG. 27 shows photographic observation of thesyringeability of comparator in hot water with a 23 gauge needle withand without a filter.

TABLE 69 Syringeability in Ambient Water with an 18 Gauge Needle andAssay of Syringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 18gauge Needle 1 5.0 57.1 1.0 9.0 18 gauge Needle 2 5.0 48.5 1.5 21.6 18gauge Needle 3 5.0 50.8 5.0 21.2 Mean 52 17 0.2 μm filter 1 2.0 23.6<1.0* 0.1 0.2 μm filter 2 2.0 25.5 <1.01* 1.2 0.2 μm filter 3 1.5 16.8<1.01* 0.6 Mean 22 1 Cotton wool 1 2.5 24.5 1.0 9.7 Cotton wool 2 4.012.8 <1.0* 7.8 Cotton wool 3 1.0 42.5 1.75 12.0 Mean 27 10 Cig filter 15.0 53.6 5.0 4.6 Cig filter 2 5.0 40.2 5.0 6.1 Cig filter 3 5.0 52.7 1.05.0 Mean 49 5 *Samples <1 ml not required to be tested according to theprotocol however they were analyzed at formulation development requestfor information only and have been reported here for information only.

TABLE 70 Syringeability in Hot Water with an 18 Gauge Needle and Assayof Syringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 18gauge Needle 1 5.0 56.7 4.0 43.8 18 gauge Needle 2 5.0 50.6 4.0 52.1 18gauge Needle 3 5.0 48.3 4.0 41.4 Mean 52 46 0.2 μm filter 1 2.0 23.5<1.0* 1.3 0.2 μm filter 2 2.5 25.4 <1.0* 1.6 0.2 μm filter 3 2.0 16.7<1.0* 0.2 Mean 22 1 Cotton wool 1 <1.0* 24.3 5.0 13.9 Cotton wool 2 2.042.3 5.0 3.7 Cotton wool 3 <1.0* 12.8 5.0 6.0 Mean 26 8 Cig filter 1 4.053.3 5.0 11.7 Cig filter 2 5.0 40.0 5.0 10.3 Cig filter 3 5.0 52.3 5.012.9 Mean 49 12 *Samples <1 ml not required to be tested according tothe protocol however they were analyzed at formulation developmentrequest for information only and have been reported here for informationonly.

TABLE 71 Syringeability in Ambient Water with a 20 Gauge Needle andAssay of Syringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 20gauge Needle 1 4.0 49.1 5.0 44.3 20 gauge Needle 2 5.0 49.3 5.0 49.9 20gauge Needle 3 5.0 53.0 5.0 48.3 Mean 50 48 0.2 μm filter 1 1.0 12.3 0.2μm filter 2 1.0 16.8 0.2 μm filter 3 2.0 24.1 Mean 18 Cotton wool 1 2.020.3 1.0 10.6 Cotton wool 2 2.5 26.9 2.0 19.7 Cotton wool 3 4.0 47.8 1.05.9 Mean 32 12 Cig filter 1 5.0 51.4 Cig filter 2 5.0 51.8 Cig filter 35.0 54.7 Mean 53 Note: 0.2 μm and cigarette filter samples for prototype2 not progressed from 18 Gauge.

TABLE 72 Syringeability in Hot Water with a 20 Gauge Needle and Assay ofSyringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 20gauge Needle 1 4.0 50.6 5.0 47.8 20 gauge Needle 2 5.0 52.1 5.0 52.8 20gauge Needle 3 5.0 53.5 5.0 52.7 Mean 52 52 0.2 μm filter 1 1.0 10.5 0.2μm filter 2 1.0 11.0 0.2 μm filter 3 1.0 11.9 Mean 11 Cotton wool 1<1.0* 4.1 <1.0* 3.2 Cotton wool 2 <1.0* 9.4 1.0 5.9 Cotton wool 3 1.517.3 <1.0* 2.4 Mean 10 4 Cig filter 1 5.0 42.6 Cig filter 2 5.0 51.4 Cigfilter 3 5.0 51.6 Mean 49 *Samples <1 ml not required to be testedaccording to the protocol however they were analyzed at formulationdevelopment request for information only and have been reported here forinformation only. Note: 0.2 μm and cigarette filter samples forprototype 2 not progressed from 18 gauge.

TABLE 73 Syringeability in Ambient Water with a 23 Gauge Needle andAssay of Syringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 23gauge Needle 1 7.0 73.6 1.5 15.6 23 gauge Needle 2 4.0 43.1 4.0 37.4 23gauge Needle 3 10.0 95.8 4.0 44.4 Mean 71 32 0.2 μm filter 1 1.5 19.30.2 μm filter 2 2.0 21.7 0.2 μm filter 3 2.0 20.1 Mean 20 Cotton wool 1<1.0* 6.2 Cotton wool 2 <1.0* 6.5 Cotton wool 3 <1.0* 3.5 Mean 5 Cigfilter 1 6.0 62.9 Cig filter 2 5.0 53.6 Cig filter 3 5.0 50.7 Mean 56*Samples <1 ml not required to be tested according to the protocolhowever they were analyzed at formulation development request forinformation only and have been reported here for information only Note:0.2 μm and cigarette filter samples not progressed from 18 gauge andcotton wool from 20 gauge.

TABLE 74 Syringeability in Hot Water with a 23 Gauge Needle and Assay ofSyringed Samples Comparator Prototype 2 Volume Volume syringed/syringed/ drawn % drawn % Sample Name (mL) Recovery (mL) Recovery 23gauge Needle 1 5 61.8 3.5 46.5 23 gauge Needle 2 5 64.8 4 40.4 23 gaugeNeedle 3 5 58.0 5 49.3 Mean 62 45 0.2 μm filter 1 1.5 23.4 0.2 μm filter2 2.5 31.1 0.2 μm filter 3 1.5 17.7 Mean 24 Cotton wool 1 5 54.8 Cottonwool 2 2 22.7 Cotton wool 3 4.5 50.7 Mean 43 Cig filter 1 5 60.9 Cigfilter 2 3.5 34.4 Cig filter 3 5 57.4 Mean 51 Note: 0.2 μm and cigarettefilter samples not progressed from 18 gauge and cotton wool from 20gauge.Application of Heat—Melting Temperature

A capsule was crushed to reduce the particle size of the dose. Thecrushed capsule contents was placed in a watch glass and heated using ahot plate until melted. The temperature of melting were recorded. Anymixes that could be drawn by syringe via an 18, 20, 26 or 28-gaugeneedle were further investigated. The syringe was pre-weighed and thenre-weighed after the mix had been drawn to measure the percentageentering the syringe.

TABLE 75 Prototype 2 Drug Product Weights Following Melting and Drawinginto an 18 Gauge Needle Weight of empty Weight of Amount Amount syringeand syringe and of drug of drug needle needle after test product productSample Name (g) (g) (g) % prototype 2-1 4.94598 4.95980 0.01382 7.5prototype 2-2 4.94609 4.97653 0.03044 16.5

TABLE 76 Prototype 2 Drug Product Weights Following Melting andExpelling from an 18 Gauge Needle Weight of empty Weight of AmountAmount syringe and syringe and of drug of drug needle needle after testproduct product Sample Name (g) (g) (g) % prototype 2-1 4.95833 4.983090.02476 13.4 prototype 2-2 4.96619 4.98547 0.01928 10.4

TABLE 77 Prototype 2 Drug Product Weights Following Melting and Drawinginto a 26 Gauge Needle Weight of Amount Amount syringe of drug of drugWeight of empty after test product product Sample Name syringe(g) (g)(g) % prototype 2-1 4.95962 4.95964 0.00002 0.0 prototype 2-2 4.971934.97327 0.00134 0.7 Note - Amount of drug product % calculated asfollows: (Amount of drug product/Fill Weight (185 mg))*100

The melting point for prototype 2 was 70° C. for both samples tested.

Following melting, the drug product for both samples of prototype 2 weredrawn up into an 18 gauge needle. The drug product solidified whenremoved from the heat and drawn into the needle. None reached thesyringe.

During the expel test for prototype 2, there was only a very smallamount in the needle and none of it reached the syringe. For bothpreparations, the drug product solidified inside of the needle andnothing was expelled when pressure was applied.

Samples for prototype 2 were attempted to be drawn up into a 26 gaugeneedle however no drug product reached the needle or syringe.

For the comparator tablet, the powder was heated to 200° C. and did notmelt into a sufficient fluid to be syringed.

Syringeability After Preparation in Water and Multi-Pass Filtering

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of water at ambient temperature for up to thirtyminutes until homogenous. The solution was drawn into a syringe via an18-gauge needle. A cigarette filter was placed into the mortar andallowed to absorb any remaining liquid. The needle was placed into thecigarette filter to transfer any liquid taken up. In cases where 1 mL orgreater was drawn up and was fluid enough to be expelled through theneedle, the syringe contents was dispensed into suitably sized vessel.The filtering process was repeated a further two times or until thefluid was translucent. Where a translucent solution was produced, thesolution was dispensed into a suitably sized volumetric flasks andprepared for HPLC analysis using the standard assay method diluent.Where a translucent solution was not produced, the sample was notanalyzed.

TABLE 78 Syringeability after Preparation in Water and Multi-passFiltering % Recovery % Recovery Sample Name Comparator Prototype 2Sample 1 32.7 Not analyzed Sample 2 36.1 Not analyzed Sample 3 39.8 Notanalyzed Mean 36 —

For prototype 2, sample preparation 1 and 2: 5 ml was drawn into thesyringe on the first filter and the resulting solution was opaque. 0.5ml was drawn into the syringe on the second filter and the solution wasopaque and therefore not assayed.

For prototype 2, sample preparation 3: 3 ml was drawn into the syringeon the first filter and the resulting solution was opaque. 1.5 ml wasdrawn into the syringe on the second filter and the solution was opaqueand therefore not assayed.

For the comparator, sample preparation 1: 5 ml was drawn into thesyringe on the first filter and the resulting solution was opaque. 4.5ml was drawn into the syringe on the second filter and the solution wasopaque. 4 ml was drawn into the syringe on the third filter and thesolution was opaque. Due to the volume recovered, the sample wasanalyzed by HPLC.

For the comparator, sample preparation 2: 4 ml was drawn into thesyringe on the first filter and the resulting solution was opaque. 3 mlwas drawn into the syringe on the second filter and the solution wasopaque. 3 ml was drawn into the syringe on the third filter and thesolution was opaque. Due to the volume recovered, the sample wasanalyzed by HPLC.

For the comparator, sample preparation 3: 4 ml was drawn into thesyringe on the first filter and the resulting solution was opaque. 3.5ml was drawn into the syringe on the second filter and the solution wasopaque. 3 ml was drawn into the syringe on the third filter and thesolution was opaque. Due to the volume recovered, the sample wasanalyzed by HPLC.

Test of Syringeability (Prototype 2 and Comparator Only)

See Appendix B for a detailed description of the method used for thetest of syringeability and chemical extraction.

A capsule was crushed to reduce the particle size of the dose and thenground with 5 mL of water at ambient temperature for up to thirtyminutes until homogeneous. The mix was tested in order to ascertain ifit could be sufficiently fluid to be drawn up into a Luer-lok syringevia a 26-gauge needle. The syringe plunger was drawn back to the 5 mLmark, maintaining a maximum pressure for 30 seconds or until the syringehas equilibrated pressure. If approximately 1 mL or greater was drawninto the syringe and was fluid enough to be expelled through the needle(for injection) then the syringe contents was dispensed into a suitablysized volumetric flask and prepared for HPLC analysis using the standardassay method diluent.

The above process was repeated using narrower gauge needles (18, 20 and23 gauge) and water heated to 90-95° C.

TABLE 79 Syringeability in Ambient Water (5 mL) Comparator Prototype 2Volume Volume syringed/ syringed/ drawn % drawn % Sample Name (mL)Recovery (mL) Recovery 18 gauge Needle 1 4.0 90.4 2.0 44.5 18 gaugeNeedle 2 4.5 88.3 2.5 50.9 18 gauge Needle 3 4.5 92.2 2.5 47.4 Mean 90  48 20 gauge Needle 1 1.5 48.6 1.0 18.1 20 gauge Needle 2 1.5 59.4 1.027.1 20 gauge Needle 3 1.5 66.9 1.0 26.7 Mean 58   24 23 gauge Needle 11.5 48.7 1.0 17.1 23 gauge Needle 2 1.5 39.0 1.0 1.2 23 gauge Needle 33.0 65.2 <1.0* 19.0 Mean 51   12 26 gauge Needle 1 2.0 37.0 <1.0* 0.5 26gauge Needle 2 1.5   0** <1.0* 3.0 26 gauge Needle 3 1.0 21.6 <1.0* 1.1Mean 20   2 *Samples <1 ml not required to be tested according to theprotocol however they were analyzed at formulation development requestfor information only and have been reported here for information only.**Note 1.5 mL drawn but could not be expelled.Observations:

For the comparator tablet in ambient Water 18 Gauge Needle: All threepreparations easy to syringe and easy to expel.

For the comparator tablet in ambient water 20 Gauge Needle: All threepreparations easy to syringe and hard to expel.

For the comparator tablet in ambient water 23 Gauge Needle: All threepreparations easy to syringe and hard to expel.

For the comparator tablet in ambient water 26 Gauge Needle, samplepreparations 1 and 3 were hard to syringe and hard to expel. Samplepreparation 2 did not expel.

FIG. 28 shows photographic observations of the syringeability ofPrototype 2 in ambient water with varying gauged needles. FIGS. 29 and30 show photographic observations of the syringeability of comparatorand Prototype 2, respectively, in hot water with varying gauged needles.

TABLE 80 Syringeability in Hot Water (5 mL) Comparator Prototype 2Volume Volume syringed/ syringed/ drawn % drawn % Sample Name (mL)Recovery (mL) Recovery 18 gauge Needle 1 4.0 81.9 <1.0* 2.9 18 gaugeNeedle 2 4.0 84.9 <1.0* 17.4 18 gauge Needle 3 4.0 91.0 1.5 24.2 Mean 8615 20 gauge Needle 1 4.0 87.2 1.0 21.8 20 gauge Needle 2 4.0 87.5 <1.0*5.5 20 gauge Needle 3 4.0 94.9 1.0 26.2 Mean 90 18 23 gauge Needle 1 4.086.1 <1.0* 0.5 23 gauge Needle 2 4.0** 0 <1.0* 2.3 23 gauge Needle 3 4.093.6 <1.0* 5.8 Mean 60 3 26 gauge Needle 1 4.0 87.6 <1.0* 2.1 26 gaugeNeedle 2 3.0 64.5 <1.0* 4.3 26 gauge Needle 3 0.0 0 <1.0* 2.1 Mean 50.73 *Samples <1 ml not required to be tested according to the protocolhowever they were analyzed at formulation development request forinformation only and have been reported here for information only.**Note 4 mL drawn but could not be expelled.Abuse Involving Chemical Extraction (Prototype 2 and Comparator Only)

See Appendix B for a detailed description of the method used for thetest of chemical extraction.

Extraction in Small Volumes of Ambient 0.2% Sodium Bicarbonate Solution(Each Sample in Triplicate)

A capsule was crushed to reduce the particle size of the dose and thenground with 5 mL of 0.2% Sodium Bicarbonate solution for five minutesuntil homogeneous. The resulting suspension was transferred to ascintillation vial, the lid covered with Parafilm and shaken in a waterbath at ambient temperature. Samples were removed at 60 minutes andfiltered through a 0.45 μm filter into a flask and diluted to volumeusing the standard assay method diluent.

The filtered samples were analyzed by HPLC to quantify the API present.

The experiment was repeated using 2 mL of ambient 0.2% SodiumBicarbonate solution.

TABLE 81 Comparison of Ambient Solvent Extraction (Mean n = 3) % AssayAverage Amount Sample 0.2% Sodium 0.2% Sodium 60 Mins Bicarbonate 5 mLBicarbonate 2 mL Prototype 2 23 N/A Comparator 103 96

For prototype 2, after grinding with 5 mL ambient 0.2% sodiumbicarbonate, a thick opaque solution was obtained. After 60 mins shakingcontents were thickened and difficult to filter approximately 1 ml offiltrate collected.

For prototype 2, after grinding with 2 mL ambient 0.2% sodiumbicarbonate, a thick gel like semi solution mixture was obtained. Aftershaking unable to be filtered therefore no HPLC analysis was performed.

For comparator tablets, a salmon pink solution was obtained aftergrinding with 5 mL ambient 0.2% sodium bicarbonate which was easy tofilter after 60 mins shaking.

For comparator tablets, the crushed sample absorbed the 2 mL ambient0.2% sodium bicarbonate during grinding and shaking. After shaking, lessthan 1 mL of the filtered solution was collected.

Extraction in Small Volumes of Hot 0.2% Sodium Bicarbonate Solution(Each Sample in Triplicate).

A capsule was crushed to reduce the particle size of the dose and thenground with pre-heated 5 mL of 0.2% Sodium Bicarbonate solution for fiveminutes or until homogeneous. The resulting suspension was transferredto a scintillation vial, the lid covered with Parafilm and shaken in awater bath at ambient temperature. Samples were removed at 60 minutesand filtered through a 0.45 μm filter into a flask and diluted to volumeusing the standard assay method diluent.

Repeat the experiment using 2 mL of pre-heated 0.2% Sodium Bicarbonatesolution

TABLE 82 Comparison of Hot Solvent Extraction (Mean n = 3) % AssayAverage Amount Sample 0.2% Sodium 0.2% Sodium 60 Mins Bicarbonate 5 mlBicarbonate 2 ml Prototype 2 N/A N/A Comparator 108 109

For prototype 2, after grinding with 5 mL hot 0.2% sodium bicarbonate, aviscous opaque soft solid solution was obtained. It could not befiltered and therefore no HPLC analysis was performed.

For prototype 2, after grinding with 2 mL hot 0.2% sodium bicarbonate,a—Semi solid solution was obtained which turned solid after shaking. Themixture could not be filtered and therefore no HPLC analysis wasperformed.

No observations were recorded following grinding of the comparatortablets with 5 mL hot 0.2% sodium bicarbonate.

For the comparator tablets, the 2 mL hot 0.2% sodium bicarbonate wasabsorbed during the grinding and shaking process, which resulted in lessthan 1 mL of filtrate being collected.

Ethanol Extraction Test (Prototype 2 and Comparator Only, Prepared inTriplicate)

See Appendix B for a detailed description of the method used for thetest of chemical extraction.

A capsule was crushed to reduce the particle size of the dose and thenground with 10 mL of 95% ethanol solution for five minutes or untilhomogeneous. The resulting sample was filtered through a 0.45 μm nylonfilter into a round bottom flask. The ethanol was evaporated bytransferring the flask to a beaker containing water on a hot plate. Thenature of the resultant mixture was recorded.

For prototype 2, the filtrate after evaporation was not syringeabletherefore no HPLC analysis was performed.

For the comparator, the filtrate after evaporation was not syringeabletherefore no HPLC analysis was performed.

For prototype 2 and the comparator, the residue left in each roundbottom flask was agitated with a spatula and stuck to a spatula.

Based on the results above, it can be concluded that prototype 2 is moreresistant to abuse when compared with the comparator tablet. Thisincludes both by preventing the capsule contents to be physically groundfor insufflation or by chemical extraction followed by drying togenerate a powder residue. The risk of abuse via injection is alsoreduced, as the yields of drug recovered are much lower compared withthe comparator. It was found that the resulting prototype 2 solution wasmore difficult to draw into a syringe and expel when compared with thecomparator tablet.

Example 4: Comparison of Prototype 2, Placebo and a Non-Abuse DeterrentTablet: Texture Analysis and Rheology

listed drug (LD This example compares abuse-deterrent formulationPrototype 2 (ADAIR) to placebo and—Barr's 10 mg Immediate Releasetablet) using a texture analyzer and a rheometer.

This example demonstrates that a greater force is required to expelmanipulated ADAIR through a 26 G needle than that for the manipulatedfiltered LD through the same needle size. The data described supportsthat the abuse-deterrent formulation Prototype 2 and the placebo weremore abuse deterrent, with respect to syringeability, than the LD.

The rheology of manipulated formulations of ADAIR, placebo and LD werecharacterised using a rheometer. Manipulated LD has been found to have aviscosity profile similar to water, wherase manipulated ADAIR andplacebo were shown to have significantly higher viscosities, indicatingthat they would be more difficult to inject.

The placebo and ADAIR bulk formulations have been examined at varioustemperatures and a recommended filling temperature of 55±10° C. has beenestablished, provided there are no stability issues at this temperature.

Introduction

Prototype 2 is an immediate release (IR) abuse deterrent formulation(ADF) of dextroamphetamine, now known as ADAIR (Abuse DeterrentAmphetamine Immediate Release), for clinical trial use. ADAIR is a 10 mgformulation of dextroamphetamine sulfate with a desired immediaterelease profile comparable to the selected non-AD listed drug (LD,Barr's 10 mg IR tablet containing dextroamphetamine sulfate).

ADAIR has been formulated using Kollisolv P124 (Poloxamer 124), Gelucire48/16 (Polyoxyl stearate) and Kelcogel CGHA (gellan gum) and it isdelivered as a 10 mg dose, in a size 3 banded gelatin capsule(previously called prototype 2). The bulk mix has been filled intocapsules at 55° C.

A method capable of quantifying syringeability against a repeatableforce of injection is described. A texture analyzer (TA), equipped witha syringe testing rig, was used to quantify the force required to ejectthe manipulated formulation from the syringe after developing a suitablemethod.

In parallel to the texture analyzer syringeability (TAS) testing,viscosity assessments were performed on the samples using a BrookfieldDV-III Ultra Programmable Rheometer, in an attempt to correlate force ofinjection to rheological behaviour. The increased force required toexpel manipulated ADAIR and its manipulated placebo through a 26 Gneedle, compared to filtered LD, has been attributed to greaterviscosity.

Finally, the viscosity of the bulk ADAIR formulation, along with asuitable placebo, was measured at various temperatures between 25-65° C.in order to verify the suitability of 55° C. for filling and thedetermine the suitable range. For the placebo formulation, the API wasreplaced with Avicel PH101, and used as a surrogate forDextroamphetamine Sulfate in scale-up trials. A filling temperature of55±10° C. has been recommended for ADAIR and the placebo, provided thatthere are no concerns with thermal stability at this temperature.

Materials and Equipment

The Capsugel Edinburgh received raw material (RRM) number,manufacturer's batch number, manufacturer and expiry date for thematerials used in these studies are detailed in Table 83.

TABLE 83 Batch details for excipients used during this study. MaterialFunction Manufacturer Dextroamphetamine Sulfate API Cambrex KollisolvP124 Carrier BASF Gelucire 48/16 Carrier Gattefosse Kelcogel CGHAViscosity modifier Kelco Avicel PH101 Placebo FMC Biopolymer AvicelPC101 Placebo (method FMC Biopolymer development) 10 mgDextroamphetamine Comparator Teva Sulfate tablets

The details of needles used in this work are shown in Table 84.

TABLE 84 Batch details for needles and syringes used during this study.Material 18 gauge BD Microlance 3 26 gauge BD Microlance 3 BD 5 mLsyringe Luer-lok ™Equipment

Equipment used during these studies is detailed in Table 85.

TABLE 85 Formulation development equipment used in this work. EquipmentBalances Silverson high shear mixer Fan oven Temperature probe Stainlesssteel spatulas Vacuum desiccator PVDF 25 mm 0.45 μm syringe filterTexture Analyzer TA-XTPlus with Universal Syringe rig BrookfieldRVDV-III UCP programmable rheometer Amber glass jars Mortar and pestleStopwatch

Method

3. Placebo Formulation Preparation

To prepare the placebo bulk mix formulation for method development,materials were dispensed into a 60 mL amber jar (see

Table for quantities) and heated in an oven to melt. The bulk materialwas high shear mixed for 1 minute, during which time the temperaturereduced from 59.1 to 51.2° C. The bulk mix was then degassed in a vacuumchamber to remove air bubbles. Note that due to material availabilityAvicel PC101 was used for this work rather than PH101 which was used forsubsequent technical manufactures. These are considered physiochemicallyequivalent, with PC the grade used for personal care, and PH thepharmaceutical grade material.

TABLE 86 Dispensed quantities for the placebo bulk mix preparation formethod development. Unit Batch Lower Upper formulation Quantity limitlimit Actual Material (%) (g) (g) (g) (g) Avicel PC101 5.4054 1.081081.0757 1.0865 1.0820 Kollisolv P124 37.8378 7.56756 7.5297 7.6054 7.5424Gelucire 48/16 28.3784 5.67568 5.6473 5.7041 5.6876 Kelcogel CGHA28.3784 5.67568 5.6473 5.7041 5.6843 Total 100 20 19.9963

To prepare the placebo bulk mix for analysis, materials were dispensedinto a 60 mL jar (see Table 86) and placed in the oven prior to highshear mixing. The bulk material was high shear mixed for a total of 1min, during which time the temperature dropped from 50° C. to 42° C.

TABLE 87 Dispensed quantities for the placebo bulk mix preparation foranalysis. Unit Batch Lower Upper formulation Quantity limit limit ActualMaterial (%) (g) (g) (g) (g) Avicel PC101 5.4054 1.08108 1.0757 1.08651.0802 Kollisolv P124 37.8378 7.56756 7.5297 7.6054 7.5928 Gelucire48/16 28.3784 5.67568 5.6473 5.7041 5.6821 Kelcogel CGHA 28.3784 5.675685.6473 5.7041 5.6699 Total 100 20 20.0250

ADAIR Formulation Preparation

To prepare the active ADAIR formulation, the Kollisolv P124, Gelucire48/16 and Kelcogel CGHA were dispensed into a 60 mL amber jar (see Table88) and placed in an oven (53° C.) to melt the Gelucire 48/16. The APIwas then dispensed into the jar, mixed with a spatula to wet the powder,and the bulk material returned to the oven for 10 minutes to increasethe fluidity again prior to high shear mixing. High shear mixing wascarried out for a total of 1 min, during which the temperature reducedfrom 43° C. to 36-37° C. It was noted that the material was beginning toharden at the end of the mixing time but a homogenous mix had beenachieved prior to this.

TABLE 88 Dispensed quantities for the ADAIR bulk mix preparation foranalysis. Unit Batch Lower Upper formulation Quantity limit limit ActualMaterial (%) (g) (g) (g) (g) Dextro- 5.4054 1.08108 1.0757 1.0865 1.0789amphetamine sulfate Kollisolv P124 37.8378 7.56756 7.5297 7.6054 7.5706Gelucire 48/16 28.3784 5.67568 5.6473 5.7041 5.6774 Kelcogel CGHA28.3784 5.67568 5.6473 5.7041 5.6552 Total 100 20 19.9821

Preparation of Manipulated Samples

To prepare samples of manipulated placebo and ADAIR formulations forsyringeability and viscosity assessment, ˜1.11 g (equivalent to fillmaterial for 6 capsules) was ground in a mortar and pestle with 20 mL ofroom temperature potable water until homogenous. The manipulatedmaterial was stored in an amber glass jar prior to analysis. An attemptwas made to filter a sample of manipulated active material through aPVDF 0.45 μm syringe filter, however only a few drops of filtrate wereproduced before the filter blocked.

To prepare samples of manipulated listed drug (LD), three full tabletswere ground in 10 mL of room temperature potable water until homogenous.

Texture Analyzer Syringeability

The texture analyzer TAXTPlus was used with a Universal syringe rig and30 kg load cell. The instrument was calibrated for height and weightprior to use, and programmed for a set start position of 3 mL, and atarget distance of 9 mm. See 88for method settings. 5 mL Leur-Lok™syringes were used to prevent expulsion of the needle from the syringeduring the test, and samples were assessed (n=2 or 3, depending onavailable sample) using 18 gauge and 26 gauge needles.

During the method development phase, water and manipulated placeboformulation were analyzed, as well as empty syringes and empty syringeswith needles attached, as controls (n=2 or 3). For the sample analysis,these were included in addition to the manipulated placebo, manipulatedADAIR and manipulated LD (n=2 or 3). Syringes were back-filled, exceptfrom free-flowing liquids (water and LD samples), where the syringeswere loaded by drawing the material to be tested up through the tip,with no needle present.

TABLE 89 Texture Analyzer settings used to assess syringeability.Parameter Setting Test mode Compression Test speed 0.50 mm/s Post-testspeed 5.00 mm/s Target mode Distance Distance 9.000 mm Distance unit mmForce unit N Time unit s

Viscosity

Viscosity was assessed using a Brookfield RVDV-III Ultra Cone and Platerheometer, with geometries CP40 and CP52. Manipulated ADAIR, manipulatedplacebo and manipulated LD were analyzed at 25° C. Placebo and ADAIRbulk mixes were analyzed at 25, 35, 45, 55 and 65° C. to assess fillingtemperature. A suitable method was developed for each sample type, andshear stress was measured on application of an increasing and decreasingspeed ramp, for each sample.

Results and Discussion

4.1 Preparation of ADAIR and Placebo Formulations

The ADIAR and placebo formulations were prepared without issue.Processing was aided by pre-heating stainless steel spatulas and highshear heads prior to use. At elevated temperatures the bulk formulation,although viscous, had sufficient process-ability to facilitate mixingand aliquoting at the bench scale.

3.2 Preparation of Manipulated Samples

Grinding the comparator tablets with a mortar and pestle resulted in acoarse powder/liquid mixture with a pink/brown hue. The tablets could becrushed quickly with the mortar and pestle to aid grinding with thesolvent.

For the placebo and ADAIR, the formulations were heated to facilitatealiquoting into the mortar (FIG. 32-33 ) This was not heated prior touse and the material solidified quickly. The waxy consistency of thesolid fill material made it slightly more challenging to process using apestle. On grinding with water, a gel-like material was formed. Theplacebo formulation formed a gel with greater apparent viscosity. Thiswas likely due to the presence of Avicel PH101 which had been added toreplace the dextroamphetamine sulfate.

The quantities of materials used for the manipulations, along with thetests they were utilised for are documented in Table 90

TABLE 90 Table documenting the amount of material used for manipulation,the volume of water and grinding time used during the manipulation andwhat analysis the sample was used for. Quantity Mate- of un- Vol- Grind-rial manip- ume of ing Batch under ulated water time number testmaterial (mL) (s) Used for 1003/ Placebo 1.1239 g 20 60 Methoddevelopment 174/02 1003/ LD 3 tablets 10 64 Analysis 18 Gauge 187/06needle (unfiltered) 1003/ LD 3 tablets 10 63 Analysis 26 gauge 187/07needle (unfiltered) 1003/ Placebo 1.1167 g 20 155 Analysis 18 Gauge190/01 needle (unfiltered) 1003/ ADAIR 1.1087 g 20 148 Analysis 18 Gauge190/02 needle (unfiltered) 1003/ Placebo 1.1199 20 60 Analysis 26 Gauge190/03 1003/ ADAIR 1.1170 20 94 Attempt to filter. 190/04 Analysis 26Gauge. 1003/ LD 3 tablets 10 60 Analysis 18 Gauge 191/03 (filtered).1003/ LD 3 tablets 10 60 Analysis 26 Gauge 191/04 (filtered).

3.3 Texture Analysis Development

A method was developed which was capable of measuring the forcesassociated with injecting empty syringes with 18 G needles, emptysyringes with 26 G needles, water (with both 18 and 26 G needles) and amanipulated ADF placebo (with both 18 G and 26 G needles). Due to theviscous nature of the manipulated ADF, the syringe barrels wereback-filled, rather than drawing liquid into the syringe from the tip.for an illustration of the set-up The texture analyzer software was usedto calculate the stiction force, plateau force and end constraint. Inorder to carry this out the profile was divided into three timezones(1-2, 2-3 and 3-4 on 35below). During this test, a button triggeris used and so the data is captured from the point where the teststarts. There was an initial peak in force as the syringe plunger beginsto move and the syringe contents start to move. This is called thestiction, and is the force required to overcome the static friction.This was taken as the maximum value during the first third of theanalysis (1-2). As the test progressed and the plunger moved into thecentral area of the syringe barrel, a force plateau was reached. Theplateau force was therefore taken as the maximum force between points 2and 3 (FIG. 5 ) The final peak force was recorded as the end constraint.The average results are shown in FIG. 6 .

Texture Analyzer Syringeability

In order to remove any contribution of any constraint as a result of thesyringe barrel geometry during the analysis of the samples, the test wascarried out moving the plunger from 3 mL position to 2 mL position,rather than moved to fully expel the material from the syringe. Thismeant that any influence from the geometry of the syringe was avoided,for clarity of results, and meant that the “end constraint” was nolonger applicable.

At the start of the investigation empty syringes, syringes with 18 Gneedles and syringes with 26 G needles were analyzed (FIG. 37-38 ) toprovide data on the resistance to movement inherent to equipment beingused for the test (i.e., 5 mL syringe and needle). The empty syringegave an average peak force of 3.043 N, with the 18 G needle averaging4.146 N and the 26 G needle averaging 3.208 N. In each profile there wasan initial maxima within the first second of the test which related tothe force of stiction (the force required to set the plunger in motion).This could also be seen in the profiles for water through 18 G and 26 Gneedles FIG. 37

In order to minimise contribution of stiction from the equipmentinterfering with the test results, it was decided not to use thesestiction maxima to characterise the data. Additionally, due to thenature of the ADF materials and the manipulated tablets, the time takento reach a plateau force varied, or a smooth plateau was not achieved,meaning that the calculation of plateau force using the texture analyzersoftware was not practical.

As a result, it was decided that stiction, plateau and end constraintwere not practical for characterising the syringeability profiles andcomparing the gathered data. It was instead decided that the data shouldbe characterised using two parameters: the peak force (N), and the areaunder the force time curve (Ns, a representation of the “work done” tomove the plunger through 9 mm whilst expelling material from theneedle). In cases where the peak force was achieved at the stictionmaxima, the data was manually reprocessed to obtain the maxima achievedlater in the run. It should be noted that this applied only one repeatof the empty syringe (where the peak force was adjusted from 2.558 N to2.518 N), and one repeat of the manipulated filtered LD (where the peakforce was adjusted from 4.744 N to 4.215 N). It was anticipated thatusing the average peak force and the average area under the curve forall repeats in each test set would provide a more complete and relevantset of data than stiction, plateau force and end constraint in thisinvestigation.

Instead, the peak force and the area under the force time curve werecalculated. In cases where the peak force was found to be in the“stiction” area, the data was reprocessed manually to obtain the peakforce achieved during the main body of the test. It should be noted thatthis only applied to the empty syringe and the filtered LD.

For the unfiltered manipulated LD, the texture analyzer profiles showeda number of sharp peaks and troughs FIG. 39 This was thought to be aresult of particles of crushed tablet causing intermittent blocking ofthe needle during the test. These required greater force to dislodge(the texture analyzer is programmed to adjust force so as to maintain aconstant test speed, rather than to achieve a constant force). Thiseffect was not seen when analysing an equivalent sample using an 18 Gneedle FIG. 40 , due to the lager bore size of this needle. This effectis expected to be influenced by the degree of grinding that is appliedby the operator. Additionally, it is not expected that an abuser wouldattempt to inject the manipulated LD without filtering the materialfirst. The 18 G and 26 G data for these samples are shown separately forclarity.

The profiles obtained for the manipulated ADAIR and the manipulatedplacebo are shown in FIG. 41 and FIG. 42 respectively. In both of thesesamples the test using a 26 G needle produces an uneven profile withpeaks associated with increased resistance to syringing, compared to the18 G needle (wider bore) tests which produced a smoother profile, moretypical of syringe testing.

During manipulation of a solid oral dosage form to prepare forinjection, abusers will commonly filter the solution, rather thanattempt to inject a solution containing powdered excipients. As aresult, it was decided to filter a preparation of manipulated LD andanalyze this FIG. 43 . Note that a third repeat of the filtered LDthrough a 26 G needle could not be performed due to spillage of thesample during preparation for the test. An attempt was made to filterthe manipulated ADAIR for a comparative analysis but sufficient materialcould not be obtained to carry out this test (n=1). The peak force (N)and area under the curve (Ns) for all samples, along with calculatedaverage, standard deviation and coefficient of variation is shown isTable 91.

TABLE 91 Peak force and area under the curve for all samples analyzedusing the texture analyzer. Peak Area under force curve Sample setSample (N) (Ns) empty empty syringe 1 2.518 40.774 syringe empty syringe2 2.957 43.970 empty syringe 3 3.655 52.193 Average: 3.043 45.646 S.D.0.573 5.891 Coef. of Variation 18.831 12.906 empty empty syringe 18 Gneedle 1 3.438 55.098 syringe 18 G empty syringe 18 G needle 2 4.24864.250 empty syringe 18 G needle 3 4.751 70.027 Average: 4.146 63.125S.D. 0.662 7.528 Coef. of Variation 15.977 11.925 empty empty syringe 26G needle 1 3.227 42.479 syringe 26 G empty syringe 26 G needle 2 3.04847.548 empty syringe 26 G needle 3 3.349 51.635 Average: 3.208 47.221S.D. 0.151 4.587 Coef. of Variation 4.714 9.714 water 18 G water 18 G 14.874 77.436 water 18 G 2 4.836 78.184 water 18 G 3 4.766 72.757Average: 4.825 76.126 S.D. 0.054 2.942 Coef. of Variation 1.127 3.864water 26 G water 26 G 1 4.611 72.605 water 26 G 2 3.219 50.935 water 26G 3 4.503 70.161 Average: 4.111 64.567 S.D. 0.774 11.869 Coef. ofVariation 18.833 18.382 LD LD unfiltered 18 G 1 3.909 50.858 unfiltered18 G LD unfiltered 18 G 2 4.409 66.376 LD unfiltered 18 G 3 4.441 68.532Average: 4.253 61.922 S.D. 0.298 9.642 Coef. of Variation 7.017 15.571LD LD unfiltered 26 G 1 61.400 66.921 unfiltered 26 G LD unfiltered 26 G2 296.633 1457.148 LD unfiltered 26 G 3 156.687 334.931 Average: 171.573619.667 S.D. 118.321 737.556 Coef. of Variation 68.962 119.025 ADAIR 18G ADAIR 18 G 1 4.937 70.267 ADAIR 18 G 2 3.784 63.791 ADAIR 18 G 3 4.52473.589 Average: 4.415 69.216 S.D. 0.584 4.983 Coef. of Variation 13.2347.199 ADAIR 26 G ADAIR 26 G 1 49.546 265.710 ADAIR 26 G 2 40.375 308.208ADAIR 26 G 3 36.644 298.530 Average: 42.188 290.816 S.D. 6.639 22.274Coef. of Variation 15.738 7.659 LD LD filtered 18 G 1 3.692 61.637filtered 18 G LD filtered 18 G 2 2.954 47.169 LD filtered 18 G 3 3.25352.503 Average: 3.300 53.770 S.D. 0.371 7.317 Coef. of Variation 11.24513.607 LD LD filtered 26 G 1 4.215 71.760 filtered 26 G LD filtered 26 G2 4.167 70.514 LD filtered 26 G 3 — — Average: 4.191 71.137 S.D. 0.0340.881 Coef. of Variation 0.809 1.238 Placebo 18 G Placebo 18 G 1 31.051371.164 Placebo 18 G 2 38.233 320.998 Placebo 18 G 3 21.789 355.033Average: 30.358 349.065 S.D. 8.244 25.610 Coef. of Variation 27.1557.337 Placebo 26 G Placebo 26 G 1 299.455 2408.156 Placebo 26 G 2116.775 1225.739 Placebo 26 G 3 66.343 953.722 Average: 160.858 1529.206S.D. 122.649 773.249 Coef. of Variation 76.247 50.565

The graphs of average peak force for samples measured using 18 G and 26G needles are shown in FIGS. 44 and 45 , respectively. The graphs ofaverage area under curve for samples measured using 18 G and 26 Gneedles are shown in FIG. 46 and FIG. 47 , respectively.

Discussion of TA Data

The data for the 18 G needles do not show a significant differencebetween the ADAIR formulation and water for either average peak forceFIG. 48 or average area under curve FIG. 49 however this is a large boresize and unlikely to be used for intravenous abuse of dextroamphetaminesulfate.

The data obtained using a 26 G needle show a more pronounced differencebetween the manipulated ADAIR versus both water and the filtered LD foraverage peak force (FIG. 50 ) and average area under the curve (FIG. 51). This suggests that using this more appropriate needle bore size, theADAIR formulation provides a greater barrier to syringing than thefiltered LD, under these conditions. Additionally, it was not possibleto obtain enough filtrate from the manipulated ADAIR to carry out thetest on a filtered sample. This inherent barrier to filtering providedby the ADAIR excipients is therefore expected to reduce appeal ofinjecting this material, to the majority of abusers. In the eventhowever that an abuser attempts to inject the manipulated ADAIR withouta filtration step, this material would be significantly more difficultto inject than the filtered manipulated LD (average peak force 42.188 Nc.f. 4.191 N for the filtered LD, and average work done of 290.816 Nsc.f. 71.137 Ns for the filtered LD). Comparing the texture analyzerprofiles for the samples it can be seen that the filtered manipulated LDshares a similar smooth force vs time profile to potable water (in asimilar order of magnitude), whereas the manipulated LD required higherforces to depress the plunger than both water and the manipulatedfiltered LD for the duration of the tests. A rough profile with multiplepeaks suggests that this material would not be associated with a smoothinjection, which may also affect “likeability” to a potential abuser.

Rheology of Manipulated Samples

Sample rheology was examined by measuring the shear stress during anincreasing and decreasing speed ramp. For the manipulated ADAIR andplacebo, the small spindle (CP-52) was required. This is used for highviscosity samples. For water and the manipulated LD, a larger spindle(CP-40) was required. This spindle is used for low viscosity samples.The data acquired for each sample are shown in Tables 92 to 100.

Two separate samples of unfiltered manipulated LD were analyzed, alongwith two separate samples of filtered LD and a single water sample (FIG.54 ). Whilst the unfiltered manipulated LD had a higher maximum measuredviscosity than the water control (2.16 and 2.35 cP, cf. 1.33 cP at 166.7RPM) this was still in a similar order of magnitude to the water samplesand both displayed similar profiles. The unfiltered LD showed a degreeof hysteresis, which may have been a result of the presence of solidmaterial in the sample shifting and aligning during the course of thetest. The filtered LD shared a similar profile, but with less hysteresisand a viscosity more comparable to the water sample (1.53 and 1.45 cP at83.33 RPM c.f. 1.33 cP at 166.7 RPM). This suggested that themanipulated LD had a similar rheology to water, with slight increase inviscosity when unfiltered. This supports the hypothesis that the higherforces required to syringe the manipulated LD are due to particulates ofground undissolved dosage form blocking the syringe, rather than highviscosity of the manipulated material.

TABLE 92 Rheology data for manipulated unfiltered LD, measured at 25°C., repeat 1. manipulated unfiltered LD Viscosity Speed Torque ShearStress Shear Rate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 0.00 0.00 −0.9 0.000.00 1.61 83.33 4.1 10.06 624.98 1.63 166.70 8.3 20.36 1250.25 1.48250.00 11.3 27.71 1875.00 1.61 166.70 8.2 20.11 1250.25 2.16 83.33 5.513.49 624.98 0.00 0.00 −1.4 0.00 0.00

TABLE 91 Rheology data for manipulated unfiltered LD, measured at 25°C., repeat 2. manipulated unfiltered LD Viscosity Speed Torque ShearStress Shear Rate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 0.00 0.00 −2.0 0.000.00 1.88 83.33 4.8 11.77 624.98 1.59 166.70 8.1 19.87 1250.25 1.37250.00 10.5 25.75 1875.00 1.59 166.70 8.1 19.87 1250.25 2.35 83.33 6.014.71 624.98 0.00 0.00 0.0 0.00 0.00

TABLE 92 Rheology data for manipulated filtered LD, measured at 25° C.,repeat 1. Manipulated filtered LD Viscosity Speed Torque Shear StressShear Rate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 0.00 0.00 −0.4 0.00 0.00 1.5383.33 3.9 9.56 624.98 1.26 166.70 6.4 15.70 1250.25 1.32 250.00 10.124.77 1875.00 1.33 166.70 6.8 16.68 1250.25 1.37 83.33 3.5 8.85 624.980.00 0.00 −1.1 0.00 0.00

TABLE 93 Rheology data for manipulated filtered LD, measured at 25° C.,repeat 2. Manipulated filtered LD Viscosity Speed Torque Shear StressShear Rate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 0.00 0.00 −1.3 0.00 0.00 1.4583.33 3.7 9.07 624.98 1.24 166.70 6.3 15.45 1250.25 1.23 250.00 9.423.05 1875.00 1.28 166.70 6.5 15.94 1250.25 1.41 83.33 3.6 8.83 624.980.00 0.00 −0.2 0.00 0.00

TABLE 94 Rheology data for water, measured at 25° C., single repeat.water Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%)(D/cm²) (sec⁻¹) 0.00 0.00 −0.4 0.00 0.00 1.26 83.33 3.2 7.85 624.98 1.10166.70 5.6 13.73 1250.25 1.11 250.00 8.5 20.85 1875.00 1.12 166.70 5.713.98 1250.25 1.33 83.33 3.4 8.34 624.98 0.00 0.00 −0.1 0.00 0.00

For the manipulated ADAIR and placebo samples, a different speed rampwas required for each sample, indicating a degree of variability in therheological behaviour. This is not unexpected, due to the nature of theexcipients and the variability involved in manipulating an ADF.

Two separate samples of manipulated ADAIR were analyzed (Tables 97, 98and). Although the manipulated ADAIR showed shear-thinning behaviour(reduced resistance to flow under increased shear), the measuredviscosity remained higher than even the unfiltered manipulated LD, withmaximum viscosities of 6052.42 and 8334.48 cP at 1 RPM, c.f. maximumviscosities of 2.16 and 2.35 cP for the unfiltered manipulated LD.Additionally, there was hysteresis in both manipulated ADAIR viscositymeasurements, with higher readings on the down ramp. This suggests thatthe manipulated ADAIR may display a time-dependent increase inviscosity. If this is the case, this could indicate that the longer thematerial is manipulated for (eg longer grinding time), the more viscousit would become. This could be investigated further by applying aconstant shear rate for an extended time, rather than applying a speedramp.

TABLE 95 Rheology data for manipulated ADAIR measured at 25° C.,repeat 1. Manipulated ADAIR Viscosity Speed Torque Shear Stress ShearRate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 5258.66 1.00 5.3 105.17 2.00 288.2184.00 24.4 484.19 168.00 210.92 167.00 35.5 704.46 334.00 215.51 250.0054.3 1077.53 500.00 283.40 167.00 47.7 946.56 334.00 421.69 84.00 35.7708.43 168.00 6052.42 1.00 6.1 121.05 2.00

TABLE 96 Rheology data for manipulated ADAIR measured at 25° C., repeat2. Manipulated ADAIR Viscosity Speed Torque Shear Stress Shear Rate (cP)(RPM) (%) (D/cm²) (sec⁻¹) 7540.72 1.00 7.6 150.81 2.00 425.88 67.33 28.9573.49 134.66 304.26 133.70 41.0 813.60 267.40 288.73 200.00 58.21154.92 400.00 375.51 133.70 50.6 1004.11 267.40 583.56 67.33 39.6785.82 134.66 8334.48 1.00 8.4 166.69 2.00

The manipulated placebo samples also appeared to show shear thinningbehaviour with a time-dependent increase in viscosity (FIG. 56A-B). Ingeneral, the viscosity of these samples was very high, with maximummeasured viscosities of 12501.72 cP at 0.50 RPM and 1478378.00 cP at0.01 RPM. This increased viscosity is expected to be due to Avicel PH101particles dispersed in the hydrated matrix during the manipulation. Itis also possible that the out-of-trend decrease in shear stress at thetop end of the speed ramp on these samples was due to the plate/sampleslipping during the test. This was further suggested when the placebosample was examined at the end of the test and found to have moved inrelation to the cone and plate, suggesting that movement of the spindlehad relocated the sample, rather than the plate spinning on top of it.This may have been as a result of high cohesive forces in the sample.

TABLE 97 Rheology data for manipulated placebo, measured at 25° C.,repeat 1. Manipulated placebo Viscosity Speed Torque Shear Stress ShearRate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 37505.16 0.50 18.9 375.05 1.0027092.41 1.67 45.6 904.89 3.34 10272.60 2.83 29.3 581.43 5.66 7218.264.00 29.1 577.46 8.00 7117.19 2.83 20.3 402.83 5.66 5228.36 1.67 8.8174.63 3.34 12501.72 0.50 6.3 125.02 1.00

TABLE 100 Rheology data for manipulated placebo, measured at 25° C.,repeat 2. Manipulated placebo Viscosity Speed Torque Shear Stress ShearRate (cP) (RPM) (%) (D/cm²) (sec⁻¹) 0.00 0.01 −3.0 0.00 0.02 52262.421.01 53.2 1055.70 2.02 33089.87 2.00 66.7 1323.59 4.00 19414.05 3.0058.7 1164.84 6.00 21431.52 2.00 43.2 857.26 4.00 24952.36 1.01 25.4504.04 2.02 1478378.00 0.01 14.9 295.68 0.02

Filling Temperature Determination

In order to investigate the rheological behaviour of the ADAIR andplacebo formulation bulk mixes and recommend a filling temperature, bothbulk mixes were examined at various temperatures. The rheological datafor the placebo at 65, 55 and 45° C. are shown in Table below. Therheological data for the ADAIR formulation at 65, 55 and 45° C. areshown in Tables below. The viscosity plot for the ADAIR formulation isshown in FIG. 58 . An attempt was made to measure the placebo sample at35° C. but the maximum torque level was exceeded immediately, suggestingthat the material had become solid or close to solid.

These data indicate that both the placebo and ADAIR formulations haverelatively high viscosity for liquid-filled hard capsule formulations,with a maximum measured viscosity of 5099.91 cP for the placeboformulation and 4504.59 cP for the ADAIR formulation (both measured at5.00 RPM, 45° C.). Both formulations are also thermosoftening, withreduced viscosity upon increased temperature. The reduction in viscositywith increased rate of shear indicate that they are both shear thinning.As a result, it is recommended that the bulk mix remains under stirringduring the filling process in order to optimise flow characteristics andprocess-ability. Additionally, both the placebo and ADAIR formulationsshow a hysteresis between the measurements obtained in the increasingspeed ramp and those obtained on the decreasing speed ramp. Unlike themanipulated formulation, these show reduced viscosity on the downwardspeed ramp, c.f. the increasing ramp. This suggests a time dependenteffect whereby viscosity is reduced when the time of stirring increases.This is known as thixotropy, and is a common behaviour in suspensions.These data indicate that although the formulation becomes morechallenging to handle (less process-able) when manipulated with water,the bulk mixes can be processed well with the application of heat andstirring. Provided that there is no stability issue, a target fillingtemperature of 55±10° C. will be suitable for both the placebo and ADAIRformulations, with constant stirring of the filling machine hopper.

TABLE 82 Rheology data for placebo formulation, measured at 65° C.Placebo 65° C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM)(%) (D/cm²) (sec⁻¹) 2695.48 6.00 16.3 323.46 12.00 1859.07 19.00 35.6706.45 38.00 1516.21 32.00 48.9 970.37 64.00 1314.11 45.00 59.6 1182.7090.00 1404.58 32.00 45.3 898.93 64.00 1566.63 19.00 30.0 595.32 38.001918.25 6.00 11.6 230.19 12.00

TABLE 103 Rheology data for placebo formulation, measured at 55° C. 55°C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%) (D/cm²)(sec⁻¹) 3952.26 6.00 23.9 474.27 12.00 2716.36 15.67 42.9 851.31 31.342244.50 25.33 57.3 1137.06 50.66 1876.68 35.00 66.2 1313.67 70.001974.22 25.33 50.4 1000.14 50.66 2171.82 15.67 34.3 680.65 31.34 2579.726.00 15.6 309.57 12.00

TABLE 104 Rheology data for placebo formulation, measured at 45° C. 45°C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%) (D/cm²)(sec⁻¹) 5099.91 5.00 25.7 509.99 10.00 3939.03 10.00 39.7 787.81 20.003360.25 15.00 50.8 1008.08 30.00 2971.64 20.00 59.9 1188.66 40.003214.73 15.00 48.6 964.42 30.00 3413.17 10.00 34.4 682.63 20.00 3790.205.00 19.1 379.02 10.00

TABLE 9 Rheology data for ADAIR formulation, measured at 65° C. ADAIR65° C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%)(D/cm²) (sec⁻¹) 2745.09 6.00 16.6 329.41 12.00 1780.74 19.00 34.1 676.6838.00 1413.89 32.00 45.6 904.89 64.00 1186.23 45.00 53.8 1067.61 90.001280.56 32.00 41.3 819.56 64.00 1477.86 19.00 28.3 561.59 38.00 2083.626.00 12.6 250.03 12.00

TABLE 106 Rheology data for ADAIR formulation, measured at 55° C. ADAIR55° C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%)(D/cm²) (sec⁻¹) 3902.65 6.00 23.6 468.32 12.00 2665.71 15.67 42.1 835.4331.34 2150.48 25.33 54.9 1089.44 50.66 1822.81 35.00 64.3 1275.97 70.001946.80 25.33 49.7 986.25 50.66 2209.81 15.67 34.9 692.56 31.34 2827.776.00 17.1 339.33 12.00

TABLE 10 Rheology data for ADAIR formulation, measured at 45° C. ADAIR45° C. Viscosity Speed Torque Shear Stress Shear Rate (cP) (RPM) (%)(D/cm²) (sec⁻¹) 4504.59 5.00 22.7 450.46 10.00 3423.09 10.00 34.5 684.6220.00 2857.54 15.00 43.2 857.26 30.00 2425.93 20.00 48.9 970.37 40.002506.96 15.00 37.9 752.09 30.00 2708.71 10.00 27.3 541.74 20.00 3135.355.00 15.8 313.54 10.00

A method to measure the force required to depress the plunger of a 5 mLsyringe through 9 mm, expelling ˜1 mL of material under test, has beenestablished. This method had been used to measure the forces required tosyringe manipulated ADAIR, manipulated placebo and manipulated LD. Ithas been shown that a significantly greater force is required to expelmanipulated ADAIR through a 26 G needle than it does to expelmanipulated filtered LD (average peak force 42.188 N c.f. 4.191 N forthe filtered LD, and average work done of 290.816 Ns c.f. 71.137 Ns forthe filtered LD). This indicates that it will be more challenging for anabuser to inject manipulated ADAIR than manipulated filtered LD,demonstrating abuse deterrent characteristics of the ADAIR formulation.A sufficient volume of filtrate could not be produced filtering themanipulated ADAIR to carry out the TAS test. This indicates that itwould be challenging for an abuser to filter the manipulated ADAIRformulation, demonstrating abuse deterrent characteristics.

Examining the manipulated formulations using a rheometer found that themanipulated filtered and unfiltered LD had similar rheological behaviourto water. Presence of undissolved material in the unfiltered LDmanifested as hysteresis between the viscosities measured during theincreasing and decreasing speed ramp. This data was in agreement withthe assumption that higher syringing forces measured for the unfilteredmaterial through the 26 G needle in the TA assessments was due toblocking of the needle with larger undissolved particulates (a result ofgrinding the tablet), rather than high viscosity. The manipulated ADAIRformulation was found to have higher viscosity than even the unfilteredmanipulated LD, with maximum viscosities of 6052.42 and 8334.48 cP at 1RPM, c.f. maximum viscosities of 2.16 and 2.35 cP for the unfilteredmanipulated LD. Both the manipulated ADAIR and manipulated placebo werefound to be shear thinning (reduced viscosity with increased shearrate), but there was evidence to suggest that increased manipulationtime could result in increased viscosity. Measuring viscosity for anextended time at a constant spindle speed could be used to investigatethis further, if required.

A rheological evaluation of the placebo and ADAIR formulations atvarious fill temperatures has established a recommended fill temperatureof 55±10° C., with constant stirring recommended to optimise flowcharacteristics. A thermal hold study has been carried out during atechnical manufacture (report to follow), whereby the bulk mix was heldand sampled at the filling temperature. For additional confidence in thesuggested filling temperature limits, it is suggested that a thermalhold study be carried out at the highest limit of the fill temperaturerange, 65° C.

Example 5: Comparison of Prototype 2 and a Non-Abuse Deterrent Tablet:Dissolution Studies

This example compares dissolution profiles of abuse-deterrentformulation Prototype 2, also known as abuse deterrence amphetamineimmediate release (ADAIR) capsule 10 mg of Dextroamphetamine Sulfate, tothe reference listed drug (LD) Dextroamphetamine sulfate 10 mg tablets.

1. Introduction

Method parameters for dissolution assessment of selected prototypeformulations with that of the LD are described in this example.Prototype formulations that were used in the method development arelisted in Table 106:

TABLE 108 Composition of prototypes 1, 2 (ADAIR), 4, 5 and 6 BatchNumber 1003/ 1003/ 1003/ 1003/ 1003/ 57/01 141/01 57/04 57/05 57/06prototype No 2 1 (ADAIR) 4 5 6 Component % Fill % Fill % Fill % Fill %Fill Dextroamphetamine 5.5 5.5 5.5 5.5 5.5 Sulfate Poloxamer P124 37.8Gelucire 48/16 28.4 56.7 Kelcogel CGHA 28.4 37.8 CMC 7H3SF Kolliphor EL56.7 Luxura 37.8 Kolliphor RH40 56.2 Xantural 75 37.8 Kollisolv 124 56.7Capsule Shell Size 3 Size 3 Size 3 Size 3 Size 3 and Size gelatingelatin gelatin gelatin gelatin Total 100 100 100 100 100

2. Analytical Methodology

The analytical conditions given in the USP method for the analysis ofDextroamphetmaine Sulfate Tablets, USP39 (see Appendix A) were used asthe starting point in the development of a suitable dissolution methodfor the analysis and comparison of the LD with Prototypes prototype1,2,4,5 and 6.

Following on from these initial development activities, a set ofparameters for the dissolution method were established and these aregiven in Appendix F. The mobile phase and reagent preparation as statedin this draft method have been used during the development activitiesunless otherwise stated within the following sections.

3. Method Development

3.1 Dissolution of 10 mg LD n=6 in 0.01M HCl using Apparatus 1

Initial method development analysis was conducted using USP dissolutionapparatus 1 and the LD-Barr's 10 mg IR tablet containingDextroamphetamine sulfate.

Dissolution Conditions as Follows for Dissolution Section 3.1

Dissolution Apparatus USP apparatus I Filter Type 40 μm probe filterMedium Type 0.01M HCl Medium Volume 500 ml Sample Times 5, 10, 15, 20,30 and 45 minutes. Sample Volume 1.5 ml (filter not replaced) straightto vial. Vessel Temperature 37° C. ± 0.5° C. Speed 100 rpm

-   -   Observations during dissolution: At the end of the test a small        amount of tablet residue remained.

HPLC Conditions as Follows for Dissolution Section 3.1

-   -   Column—Agilent Zorbax Eclipse XDB-C18 5 um 4.6×250 mm,        SN/USHR009398 (Development column)    -   Flow rate—1.5 ml/min    -   Injection volume—100 μl    -   Column temperature—40° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase    -   Run time—20 min

TABLE 107 10 mg LD in 0.01M HCl on Apparatus 1 Time % Release (min) Pot1 Pot 2 Pot 3 Pot 4 Pot 5 Pot 6 Mean RSD 5 27.10 27.63 29.51 30.76 24.7125.33 27.5 8.5 10 44.05 45.44 52.32 52.16 42.32 42.48 46.5 9.9 15 58.8060.36 66.95 71.93 55.81 56.21 61.7 10.4 20 72.99 81.80 81.01 90.40 69.4768.12 77.3 11.1 30 98.56 103.49 98.68 100.83 96.74 92.27 98.4 3.9 45100.55 103.48 98.37 100.52 102.39 95.56 100.1 2.8

3.2 HPLC Condition Method Development

Initial results for the dissolution test on Apparatus 1 in section 3.1were conducted with a development column. The next step of the HPLCmethod development was to purchase new project specific columns and tocheck that the method conditions were still suitable and reproducible.

HPLC Conditions as Follows for Section 3.2

-   -   Column—Agilent Zorbax Eclipse XDB-C18 Sum 4.6×250 mm,        SN/USNH041812 (#632)    -   Flow rate—1.5 ml/min    -   Injection volume—100 μl    -   Column temperature—40° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase 1    -   Run time—20 min

Chromatography evaluation of the new column showed that the new columnswere suitable for use. The only difference between the developmentcolumn and the new columns was the retention time of the main peak wasnow at approx. 14 mins compared to 11 mins.

3.3 Dissolution of Prototypes Prototype 1, 4, 5 and 6 in 0.01M HCl usingApparatus 1

Initial method development analysis for the prototypes was conductedusing USP dissolution apparatus 1 and prototypes 1, 4, 5 and 6.

Dissolution Conditions as follows for Dissolution Section 3.1

Dissolution Apparatus USP apparatus I Filter Type 40 μm probe filterMedium Type 0.01M HCl Medium Volume 500 ml Sample Times 5, 10, 15, 20,30 and 45 minutes. Sample Volume 1.5 ml (filter not replaced) straightto vial. Vessel Temperature 37° C. ± 0.5° C. Speed 100 rpm

Description

Analysis on each prototype was performed in triplicate.

Prototype 1

At the end of the dissolution the capsule shell and the majority of thecapsules slug appeared to have dissolved. Therefore all time points wereselected to be analyzed. However due to problems with the guar gumblocking the column only the 5 and 10 min time points were able to berun on the HPLC.

Prototypes 4, 5 and 6

At the end of the dissolution only a small portion of the capsules haddissolved and so only the 45 min time point was analyzed.

HPLC Conditions as Follows for Dissolution 3.1

-   -   Column—Agilent Zorbax Eclipse XDB-C18 Sum 4.6×250 mm,        SN/USHR009398 (Development column)    -   Flow rate—1.5 ml/min    -   Injection volume—100 μl    -   Column temperature—40° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase    -   Run time—20 min

TABLE 109 10 mg prototype 1 in 0.01M HCl on Apparatus 1 Sample Name %Release Mean % Release % RSD prototype 1 5 minutes pot 1 6.31 6.0 4.9prototype 1 5 minutes pot 2 5.79 prototype 1 5 minutes pot 3 5.81prototype 1 10 minutes pot 1 20.19 21.5 13.9 prototype 1 10 minutes pot2 19.42 prototype 1 10 minutes pot 3 24.93

TABLE 110 10 mg prototype 4 in 0.01M HCl on Apparatus 1 Sample Name %Release Mean % Release % RSD prototype 4 45 minutes pot 4 43.99 48.8 9.9prototype 4 45 minutes pot 5 53.62 prototype 4 45 minutes pot 6 48.85

TABLE 111 10 mg prototype 5 in 0.01M HCl on Apparatus 1 Sample Name %Release Mean % Release % RSD prototype 5 45 minutes pot 1 15.69 14.013.1 prototype 5 45 minutes pot 2 14.31 prototype 5 45 minutes pot 312.05

TABLE 112 10 mg prototype 6 in 0.01M HCl on Apparatus 1 Sample Name %Release Mean % Release % RSD prototype 6 45 minutes pot 4 23.46 25.214.4 prototype 6 45 minutes pot 5 22.75 prototype 6 45 minutes pot 629.35

3.4 Dissolution of 10 mg LD and Prototype 2 30 mg in 0.01M HCl usingApparatus 3 at 30 DPM

Dissolution testing of the ADAIR was carried out using Apparatus 3 withreciprocating cylinder. An initial dip rate of 30 DPM (dips per minute)was selected again due to previous experience of its use.

Dissolution Conditions as Follows for Section 3.4:

Dissolution Apparatus USP apparatus III Filter Type 40/35 μm probefilter Medium Type 0.01M HCl Medium Volume 250 ml Sample Times 5, 10,15, 20, 30 and 45 minutes. Sample Volume 2 ml (filter not replaced)Vessel Temperature 37° C. ± 0.5° C. Dip Rate 30 dips per minute MeshScreen Size 840 micron

-   -   Observations during dissolution: Tablets in all pots dissolved        between 5-10 mins with a fine orange powder settled to bottom of        the pot.

HPLC Conditions as Follows for Section 3.4

-   -   Column—Agilent Zorbax Eclipse XDB-C18 5 um 4.6×250 mm,        SN/USNH041816 (#661)    -   Flow rate—2 ml/min    -   Injection volume—100 μl    -   Column temperature—50° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase    -   Run time—16 min

TABLE 113 10 mg LD in a size 00 shell n = 6 in 0.01M HCl using Apparatus3 at 30 DPM TIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average %RSD 5 72.08 75.48 70.75 91.13 73.10 79.37 77.0 9.8 10 95.00 94.65 98.16102.09 93.24 103.50 97.8 4.3 15 105.76 104.63 107.04 103.03 103.40110.52 105.7 2.6 20 106.05 104.55 107.16 102.55 103.20 110.57 105.7 2.830 105.30 103.82 106.62 102.05 102.80 109.77 105.1 2.7 45 104.82 103.63105.84 101.26 101.97 108.97 104.4 2.7

TABLE 114 30 mg Prototype 2 0.01M HCl using Apparatus 3 at 30 DPM Boofref: 1050/109 TIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average %RSD 5 28.77 25.95 23.12 18.41 20.48 18.01 22.46 19.2 10 59.97 57.4353.93 49.84 55.04 52.40 54.77 6.6 15 79.85 79.86 74.91 72.57 73.50 72.4375.52 4.6 20 89.34 93.57 91.09 85.29 88.49 89.14 89.49 3.1 30 96.10100.76 101.23 97.44 99.28 99.53 99.06 2.0 45 97.56 102.63 102.41 100.61100.33 100.85 100.73 1.8

3.5 Dissolution of 10 mg LD and Prototype 2 30 mg n=6 in 0.01M HCl usingApparatus 3 at 5 DPM

Following on from section 3.4, the effect of dip rate on the dissolutionrate and % recovery of the LD was further evaluated by a change in diprate from 30 DPM to 5 DPM. Further to analysis of the LD at 5 DPM the LDwas encased within a size 0 gelatin capsule shell in order to replicatethe effect of the capsule shell on dissolution rate and % recoveryresults.

Dissolution Conditions as Follows for Section 3.5

Dissolution Apparatus USP apparatus III Filter Type 40/35 μm probefilter Medium Type 0.01M HCl Medium Volume 250 ml Sample Times 5, 10,15, 20, 30 and 45 minutes. Sample Volume 2 ml (filter not replaced)Vessel Temperature 37° C. ± 0.5° C. Dip Rate 5 dips per minute MeshScreen Size 840 micron

-   -   Observations during dissolution: 5-15 minutes a fine dispersion        was observed.        -   At 15 mins pots 1, 2, and 6 fully dissolved with a small            residue remained for all other pots.        -   At 20 mins pots 3 and 4 fully dissolved.        -   A small residue remained for pot 5 at 30-45 mins.

HPLC Conditions as Follows for Section 3.

-   -   Column—Agilent Zorbax Eclipse XDB-C18 Sum 4.6×250 mm,        SN/USNH041816 (#661)    -   Flow rate—2.0 ml/min    -   Injection volume—100 μl    -   Column temperature—50° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase1    -   Run time—15 min

TABLE 115 10 mg LD n = 6 in 0.01M HCL using Apparatus 3 at 5 DPM TIME(Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 46.83 43.2242.60 44.77 33.82 51.57 43.8 13.4 10 72.42 71.19 69.82 69.21 57.96 80.1170.1 10.2 15 102.00 103.47 96.36 92.35 90.72 103.47 98.1 5.8 20 107.28107.61 105.04 104.30 105.88 109.17 106.5 1.7 30 109.00 109.28 104.99109.35 109.54 108.85 108.5 1.6 45 109.14 109.52 105.08 110.77 109.71109.02 108.9 1.8

TABLE 116 10 mg LD in a size 00 shell n = 6 in 0.01M HCL using Apparatus3 at 5 DPM TIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD5 15.10 14.54 11.49 13.61 15.90 23.27 15.7 25.7 10 51.03 27.53 38.5642.72 44.83 57.31 43.7 23.6 15 87.47 49.53 75.86 80.62 78.24 94.37 77.719.8 20 106.31 70.66 98.63 101.77 102.20 106.34 97.7 13.9 30 108.8999.28 104.67 108.42 108.87 106.70 106.1 3.5 45 108.61 109.54 104.74108.33 108.93 106.11 107.7 1.7

TABLE 117 Prototype 2 30 mg 0.01M HCL using Apparatus 3 at 5 DPM TIME(Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 6.96 3.704.71 2.95 1.61 3.88 4.0 45.3 10 27.21 12.77 14.86 9.36 5.33 12.03 13.654.7 15 50.04 31.21 36.48 18.76 20.48 27.51 30.7 37.5 20 75.22 67.0362.85 47.91 52.63 54.68 60.1 16.9 30 91.71 90.43 87.05 76.45 83.36 80.6384.9 6.9 45 95.50 95.64 97.67 92.59 98.59 97.54 96.3 2.2

3.6 Dissolution of 10 mg Tablets in a Size 00 shell n=6 in 0.01M HCLusing Apparatus 3 at 5 DPM using the Gemini Column

The experiment performed in section 3.9 was repeated using the newGemini column.

Dissolution Conditions as Follows for Section 3.10

Dissolution Apparatus USP apparatus III Filter Type 40/35 μm probefilter Medium Type 0.01M HCl Medium Volume 250 ml Sample Times 5, 10,15, 20, 30 and 45 minutes. Sample Volume 2 ml (filter not replaced)Vessel Temperature 37° C. ± 0.5° C. Dip Rate 5 dips per minute MeshScreen Size 840 micron

-   -   Observations during dissolution: Capsule shell breached at 2        mins. 5 mins capsule shell partially dissolved and tablet        contents exposed. 10 mins shell fully dissolved tablets reduced        in size. 15 mins tablets reduced in size further. 20 mins pots 4        and 5 fully dissolved. 30-45 mins pot 1, 2, 3, and 6 fully        dissolved.

HPLC Conditions as Follows for Section 3.10

-   -   Column—Phenomenex, Gemini C18 5 μm, 110 A, 150 mm×4.6 mm, SN:        557080-5 BN: 5520-87 (Development column)    -   Flow rate—1.5 ml/min    -   Injection volume—20 μl    -   Column temperature—50° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase    -   Run time—10 min

TABLE 118 10 mg LD in a size 00 shell n = 6 in 0.01M HCL using Apparatus3 at 5 DPM using the Gemini Column Time (min) Pot 1 Pot 2 Pot 3 Pot 4Pot 5 Pot 6 Mean RSD 5 15.94 7.36 9.36 27.53 30.43 11.36 17 57.4 1043.31 36.01 31.69 57.94 66.76 33.37 44.8 32.1 15 65.88 75.00 52.41 85.5994.59 57.73 71.9 22.7 20 87.51 95.44 71.85 96.28 101.53 83.01 89.3 12.130 94.38 100.68 97.96 97.37 101.65 99.53 98.6 2.7 45 94.11 100.55 99.3696.35 100.72 100.14 98.5 2.7

3.7 Comparison Dissolution Studies between LD and ADAIR at 5 DPM

A comparison study between the LD and ADAIR was carried out at the 5DPM.

TABLE 119 10 mg LD in 0.01M HCl using Apparatus 3 at 5 DPM TIME (Mins)POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 15.94 7.36 9.3627.53 30.43 11.36 17.0 57.4 10 43.31 36.01 31.69 57.94 66.76 33.37 44.832.1 15 65.88 75.00 52.41 85.59 94.59 57.73 71.9 22.7 20 87.51 95.4471.85 96.28 101.53 83.01 89.3 12.1 30 94.38 100.68 97.96 97.37 101.6599.53 98.6 2.7 45 94.11 100.55 99.36 96.35 100.72 100.14 98.5 2.7

TABLE 120 10 mg ADAIR (1003/141/01) in 0.01M HCl Apparatus 3 at 5 DPMTIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 3.613.44 3.88 3.98 2.63 4.04 3.6 14.7 10 13.95 20.41 20.14 13.56 8.62 24.2316.8 34.1 15 49.45 59.67 50.79 40.31 38.83 42.73 47.0 16.8 20 76.3182.97 73.18 63.35 70.13 67.84 72.3 9.5 30 101.39 102.58 94.24 87.2694.84 88.41 94.8 6.7 45 110.13 105.82 102.41 98.25 102.52 96.63 102.64.8

TABLE 121 10 mg ADAIR (1003/141/01) in 0.01M HCl Apparatus 3 at 30 DPMTIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 30.5432.32 8.90 33.47 29.34 29.33 27.3 33.6 10 75.13 76.33 64.44 71.62 79.2271.27 73.0 7.1 15 92.78 95.89 96.81 90.52 99.38 92.97 94.7 3.4 20 98.68101.63 107.96 97.42 107.70 99.12 102.1 4.6 30 98.51 101.32 107.98 97.88106.92 98.72 101.9 4.4 45 97.67 100.57 107.60 97.22 106.29 98.35 101.34.5

3.8 Comparison Dissolution Studies between LD and ADAIR

The studies carried out using Apparatus 1 in Section 3.3 did not includethe ADAIR which was not one of the abuse deterrent prototypeformulations analyzed at this time as the apparatus III method was mostappropriate to show the comparison of the different formulations undertest.

Following the decision to progress the ADAIR formulation this was testedusing the apparatus I method. The dissolution profiles for ADAIR atInitial conditions and after a period of 8 weeks being stored at 40° C.in 75% Relative humidity were obtained. At each condition thedissolution was carried out in duplicate to give a total of 12 dosageunits tested. The results are given in Tables below and showngraphically in FIG. 13 .

Dissolution of 10 mg ADAIR n=6 in 0.01M HCl using Apparatus 1

Dissolution Conditions as Follows for Dissolution Section 3.1

Dissolution Apparatus USP apparatus I Filter Type 35 μm probe filterMedium Type 0.01M HCl Medium Volume 500 ml Sample Times 5, 10, 15, 20,30 and 45 minutes. Sample Volume 1.5 ml (filter not replaced) straightto vial. Vessel Temperature 37° C. ± 0.5° C. Speed 100 rpm

Observations during dissolution: At the end of the test a lumpy solidwhite residue remained.

HPLC Conditions as Follows for Dissolution Section 3.8

-   -   Column—Agilent Zorbax Eclipse XDB-C18 Sum 4.6×250 mm,    -   Flow rate—1.5 ml/min    -   Injection volume—100 μl    -   Column temperature—40° C.    -   Detection wavelength—210 nm    -   Mobile phase—100% Mobile phase    -   Run time—20 min

TABLE 122 Average % Release for ADAIR prep A at Initial conditions TIME(Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 5.40 4.867.72 7.23 5.91 3.61 5.8 26.3 10 32.11 26.69 42.44 36.66 34.40 19.76 32.024.8 15 55.73 54.89 59.48 58.74 52.90 55.39 56.2 4.4 20 74.18 70.2775.44 80.76 68.27 71.47 73.4 6.1 30 95.04 94.42 99.27 98.98 88.76 91.9494.7 4.3 45 105.83 107.89 107.90 108.03 102.95 105.42 106.3 1.9

TABLE 123 Average % Release for ADAIR prep B at Initial conditions TIME(Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 3.92 6.558.21 5.68 5.75 6.66 6.1 23.1 10 18.37 32.46 29.63 25.98 27.23 29.89 27.318.0 15 50.06 55.45 53.28 56.69 48.56 53.75 53.0 5.9 20 66.53 70.6169.63 74.05 68.20 76.45 70.9 5.2 30 90.88 83.88 89.88 94.94 84.36 94.2489.7 5.3 45 105.70 110.55 97.94 110.79 96.56 108.48 105.0 6.0

TABLE 124 Average % Release for ADAIR prep A at 40 C. 75% RH conditionsTIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 2.714.51 4.85 3.20 4.63 5.73 4.3 26.2 10 11.95 24.04 21.95 20.93 26.36 20.4420.9 23.5 15 40.17 41.83 46.02 45.29 47.61 42.94 44.0 6.4 20 58.35 56.5559.43 59.89 64.10 64.27 60.4 5.2 30 79.74 81.55 77.67 79.70 80.94 82.0580.3 2.0 45 98.76 100.49 99.92 99.08 100.47 103.33 100.3 1.6

TABLE 125 Average % Release for ADAIR prep B at 40 C. 75% RH conditionsTIME (Mins) POT 1 POT 2 POT 3 POT 4 POT 5 POT 6 Average % RSD 5 3.595.91 4.75 5.27 2.58 2.46 4.3 29.5 10 19.08 27.84 14.35 28.60 20.87 21.0822.0 24.7 15 39.84 44.30 45.13 46.57 42.97 45.98 44.1 5.6 20 59.35 62.7462.34 64.91 64.22 62.78 62.7 3.1 30 81.53 78.58 82.18 81.97 82.37 84.6081.9 2.4 45 98.20 98.44 106.23 98.96 103.44 99.70 100.8 3.2

TABLE 126 Average % Release for LD TIME (Mins) POT 1 POT 2 POT 3 POT 4POT 5 POT 6 Average % RSD 5 27.10 27.63 29.51 30.76 24.71 25.33 27.5 8.510 44.05 45.44 52.32 52.16 42.32 42.48 46.5 9.9 15 58.80 60.36 66.9571.93 55.81 56.21 61.7 10.4 20 72.99 81.80 81.01 90.40 69.47 68.12 77.311.1 30 98.56 103.49 98.68 100.83 96.74 92.27 98.4 3.9 45 100.55 103.4898.37 100.52 102.39 95.56 100.1 2.8

4. Conclusion

From the results obtained during this study and previous abuse deterrent(AD) studies it can clearly be concluded that using Apparatus 3 provedmore conducive to the analysis of a wider range of AD formulations thanApparatus 1 and therefore was used during the development phase of theproject to determine the preferred formulation for progression. Themethod parameters set out in Appendix F were developed.

Following the selection of ADAIR as the formulation to be progressedwith, this was tested using the Apparatus 1 in order to compare theprofile to that of the LD. This data showed full release of the API fromthe ADAIR formulation at 45 minutes and at 30 minutes for the LD. Aslight time-lag may be expected due to the required disintegration ofthe capsule shell for ADAIR to allow the formulation to be released.

The results obtained for the dissolution of ADAIR with Apparatus 1 wereconsistent the LD and equivalent dissolution profiles have been shown.The method is described in Appendix G.

APPENDIX A Protocol: Evaluation of Abuse Deterrent Immediate ReleaseFormulations of Dextroamphetamine Sulfate

1. Introduction

This protocol is designed to evaluate physical and chemical barriers toabuse including susceptibility to extraction, injection, and crushing(to deter snorting) under various conditions. The outcomes from thisevaluation should enable the selection of a better-characterized leadprototype to be further developed into a final Abuse DeterrentFormulation-Immediate Release-dextroamphetamine.

2. Objectives

To evaluate the relative susceptibility to manipulation/abuse of novelprototypes of IR d-amph 10 mg liquid fill capsules (which utilize theAbusolve™ technology) as compared to a related reference product (asappropriate).

It should be noted that there is no specific relevant regulatoryguidance issued by the FDA for non-opiate drugs and therefore the testsincluded in this protocol are adopted from the FDA guidance for Opioidswith the appropriate adaptations (ref: FDA Guidance: Abuse-DeterrentOpioids—Evaluation and Labelling, April 2015). Reference is also made tothe March 2016 FDA guidance “General Principles for Evaluating the AbuseDeterrence of Generic Solid Oral Opioid Drug Products” from whichappropriate elements and approaches were also adopted.

3. Materials

All materials used should be recorded in the laboratory notebook andreported along with the results in the final report. Informationrecorded should include material name, supplier, source, batch number,expiry date and received raw material number, where appropriate.

4. Equipment

-   -   Grade A, Laboratory Glassware.    -   Coffee grinder.    -   5/6 place analytical balance.    -   Ultrasonic and shaking water baths.    -   Sieves (various sizes) and Sieve shaker.    -   Fume hood.    -   Mortars and pestles.    -   Luer-lok syringe (no black or rubber septum syringes to be        used).    -   18 to 29 gauge syringe needles.    -   Various filters.

Analytical equipment must be qualified, calibrated and maintained inaccordance with site procedures, prior to use. Details of the equipmentused (including make and model) will be recorded in laboratory notebooksor worksheets as appropriate. Where needed additional equipment may beused and will be recorded appropriately.

5. Record Keeping

All analytical work will be recorded in project specific laboratorynotebooks. A report which will include full details of all results andsubsequent evaluations against acceptance criteria will be transcriptionand calculation checked prior to issue. In addition, wherever possibleand in all testing that include manipulation of the dosage form (such assyringeability), video recording and still images will be taken andattached to the report.

6. Analytical Methods

Some evaluations are based on visual/physical assessments; othersrequire analysis of the amount of drug substance. The Analytical methodsused are based on compendial methods for Dextroamphetamine which havebeen verified for selectivity and may require limited further validationat a later stage of development. Where indicated, the method will beused (and modified as necessary) to determine either a % assay or a %release profile for Dextroamphetamine sulfate when applicable.

Dextroamphetamine sulfate extraction will be determined by the HPLCmethod detailed in SupplementI for the IR-ADF prototype products andusing the current USP tablet method for the comparator, Barr'sDextroamphetamine sulfate 10 mg.

7. Evaluation Plan

The physical/chemical deterrent methods in this protocol will beevaluated on the following prototype formulations:

mg/capsule Component Prototype 2 Prototype 3 Prototype 7Dextroamphetamine 10 10 10 sulfate Poloxamer 124 70 — — Gelucire 48/1652.5 122.5 — Kelcogel GCHA 52.5 52.5 — Kolliphor EL — — 122.5 CMC 7H3SF52.5 Capsule Shell and Size 3 gelatin Size 3 gelatin Size 3 gelatin SizeTotal fill weight (mg)* 185 185 185 *Final fill weight to be confirmedexperimentally

Barr's 10 mg Dextroamphetamine sulfate Tablets will also be evaluated asa comparator under the same test strategy.

A stepwise approach will be taken with all analyzes, initiating with“Phase I” analyzes of all three IR-ADF prototypes and the comparator,and gradually proceeding to more destructive mechanical and chemicalmanipulations, if applicable, in “Phase II” analyzes of thoseagreed-upon prototypes demonstrating appropriate AD characteristics (seesection 8 for assessment criteria). The tests performed in both phasesare summarized in the following table:

Tested Characteristic Test Type/Conditions Phase Physical Barriers toThermal pre-treatment requirement test I Crushing Coffee Grinder Test IGrinding with Flux II Extraction Barriers Extraction in small and largevolumes I of Tier 1 solvents Extraction in small and large volumes II ofTier 2 solvents Syringeability Barriers Ambient and hot syringeabilitytest in I water utilizing a 26-gauge needle Ambient and hotsyringeability test in II water utilizing 18 to 28-gauge needlesSyringeability test of melted product II Syringeability test usingmulti-pass II filtering

Physical and Chemical Abuse Resistance Testing

All testing will employ whole dose units. Physical testing will beconducted in duplicate, and all other testing in triplicate. Wherephysical testing produces poor replicates, a third test should beperformed.

7.1 Tests of Physical Barriers to Abuse by Crushing, Cutting or Grinding

Each test in this section should include five (5) whole dose units. Allprototypes as well as the comparator compound should be tested in PhaseI studies. Record any observations such as the inability to grind thematerial or pass it through the sieve due to a waxy or other physicalcharacteristic. Video/picture documentation should be included whereverpossible.

A Phase I Studies

1. Establish Requirement for Thermal Pre-Treatment

Method: Obtain one whole dose unit. Remove the shell as quickly aspossible with a scalpel then immediately after the shell is removed,grind with a coffee grinder for five (5) minutes. If product is milledto a size less than 1 mm, no thermal pre-treatment will be used.Otherwise, thermal pre-treatment will be used in all consequentanalyzes.

2. Milling with a Coffee Grinder.

Method: Where thermal pre-treatment is required, freeze the dosage unitsin a domestic freezer for 24 hrs. Remove the shells as quickly aspossible with a scalpel then immediately after the shell is removed,grind with a coffee grinder for one minute. Determine the particle sizedistribution of the 5 capsule contents by pouring them onto thefollowing sieve assembly: 1000, 500, 250, and 106 microns. Attempts canbe made to further reduce any large particles by squeezing them withyour fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

B Phase II Studies

Proceed with Phase II studies only for prototype formulations that metassessment criteria detailed in Section 8, or otherwise agreed-upon withAlcobra. No comparator product evaluation is required.

1. Grind with Flux (Flow Enhancers).

Method: Where thermal pre-treatment is required, freeze the dosage unitsin a domestic freezer for 24 hrs. Remove the shell with a scalpel asquickly as possible, transferring the contents to a mortar and pestlewith as little loss as possible. Add 0.2 g of a flow enhancer thenimmediately grind for five minutes. Flow Enhancers to be used: SodiumChloride and Talc. Repeat particle size determination and API/Excipientsegregation as described above.

7.2 Tests of Barriers to Abuse Involving Chemical Extraction

For each test use whole dose units. All prototypes and the comparatorproduct should undergo Phase I studies. Record any observations such asthe inability to filter the material due to physical properties etc.Video/picture documentation will be included wherever possible.

Tier 1 solvents: Water, Acetic Acid (8%), 0.2% Sodium Bicarbonate,Ethanol (95%), Carbonated soft drink (cola, acidic pH). Tier 2 solvents:mineral (white) spirits, ethanol 40%, Isopropyl alcohol, methanol,acetone, 0.1N HCl, 0.1N NaOH.

A. Phase I Studies:

1) Extraction in Small Volumes of Ambient Tier 1 Solvents (Prepare EachSample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of Tier 1 solvent for 5 minutesor until homogeneous. Transfer the resulting suspension to a suitablescintillation vial, cover the lid in parafilm and shake in a water bathat ambient temperature, sampling at 5, 15, 60 and 180 minutes. Filterthe sample through a 0.45 μm filter into a flask and dilute to anappropriate concentration with the standard assay method diluent.Quantify the API concentration by HPLC. Start with the comparatorproduct first, then analyze the prototype formulations. Prototypeformulations that show API concentrations greater or equal to thecomparator product should not be taken further to the hot solventextraction analysis (see Section 8).

An intermediate filtration step over Whatman filter paper (e.g. Grade 4)may be used where 0.45 μm filters become blocked. In this instance, openfunnels and vessels should be covered in parafilm during filtration tominimise evaporation and an evaporation standard, prepared as method butfiltered over Whatman should be prepared in addition to or from aportion of the assay standard.

2) Extraction in Small Volumes of Hot Tier 1 Solvents (Prepare EachSample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of pre-heated solvent for 5minutes or until homogeneous. Transfer the resulting suspension to asuitable scintillation vial, cover the lid in parafilm and shake in awater bath at the temperature indicated in Appendix II: Table I, takingsamples at 5, 15, 60 and 180 minutes. Filter the sample through a 0.45μm filter into a flask and dilute to an appropriate concentration withthe standard assay method diluent. Quantify the API concentration byHPLC, analysing the comparator product first, followed by the prototypeformulations that advanced to this stage, starting with the 180 minutesample first. Where the 180 minute sample contains greater or equalconcentrations of API than the comparator, no further testing isrequired.

As previously, an intermediate filtration step over Whatman filter paper(e.g. Grade 4) may be used where 0.45 μm filters become blocked.

3) Extraction in 100 mL of Tier 1 Solvents at an Ambient Temperature(Prepare Each Sample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with approximately 10 mL of Tier 1 solventfor 5 minutes or until homogeneous. Transfer the resulting suspension toa volumetric flask or other suitable vessel, add further solvent to atotal volume of 100 mL, cover the lid in parafilm and place on astirring plate at ambient temperature, stirring speed 50 rpm, samplingat 5, 15, 60 and 180 minutes. Filter the sample through a 0.45 μm filterinto a flask and dilute to an appropriate concentration with thestandard assay method diluent. Quantify the API concentration by HPLC.Start with the comparator product first, then analyze the prototypeformulations. Prototype formulations that show API concentrationsgreater or equal to the comparator product should not be taken furtherto the hot solvent extraction analysis (see Section 8).

As previously, an intermediate filtration step over Whatman filter paper(e.g. Grade 4) may be used where 0.45 μm filters become blocked.

4) Extraction in 100 mL of Tier 1 Solvents at Hot Temperatures (PrepareEach Sample in Triplicate).

Where the samples pass the test criteria at room temperature (section3), repeat for tests with solvents pre-heated to the appropriatetemperatures indicated in Supplement II: Table I.

B. Phase II Studies:

Repeat the procedures and instructions outlined above in Phase I for allTier 2 solvents utilizing the comparator compound and prototypes meetingcriteria or as otherwise agreed with Alcobra.

7.3 Test of Syringeability Barriers

For each test use whole dose units of both the comparator product andformulation prototypes. Record any observations such as the inability todraw the material due to physical properties etc. Video/picturedocumentation will be included wherever possible.

%. A table of needle gauges is included in Supplement III: Table I.

A. Phase I Studies:

1) Syringeability After Preparation in Ambient and Hot Water (PrepareEach Sample in Triplicate)

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of water at ambient temperaturefor up to 30 minutes or until the solution is homogenous. Test whetherthe mix becomes sufficiently fluid to be drawn up into a Luer-loksyringe via a 26-gauge needle. Draw back the syringe plunger to the 5 mLmark, maintaining a maximum pressure for 30 seconds or until the syringehas equilibrated pressure. If approximately 1 mL or greater has beendrawn into the syringe and is fluid enough to be expelled through theneedle (for injection) then dispense the syringe contents into asuitably sized volumetric flask and dilute with Assay diluent to anappropriate concentration. Quantify the amount of API available forinjection by HPLC.

If the samples pass the test criteria at room temperature as specifiedin Section 8 (<5% yield), repeat for water heated to 90-95° C.

B. Phase II Studies:

Only prototype formulations that met criteria in Phase I Studies shouldbe analyzed in Phase II studies, or unless otherwise agreed upon withAlcobra

1) Syringeability in Different Gauge Needles After Preparation withWater (Prepare Each Sample in Triplicate)

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of solvent at ambienttemperature for 5 minutes or until the solution is homogenous. Testwhether the mix becomes sufficiently fluid to be drawn up into aLuer-lok syringe via an 18-gauge needle. Draw back the syringe plungerto the 5 mL mark, maintaining a maximum pressure for 30 seconds or untilthe syringe has equilibrated pressure. If approximately 1 mL or greaterhas been drawn into the syringe and is fluid enough to be expelledthrough the needle (for injection) then dispense the syringe contentsinto a suitably sized volumetric flask and dilute with Assay diluent toan appropriate concentration. Quantify the amount of API available forinjection by HPLC.

Repeat the above, attempting to draw the fluid via a 0.22 μm filter, awad of cotton wool and a cigarette filter tip. A fresh sample should beprepared for each filter used.

Repeat the above experiment using a narrower gauge needle for anysamples that were syringeable with the 18-gauge needle and progress viathe 20 and 23 gauge needles as long as the recovered quantity of API isgreater than 5%.

If the samples pass the test criteria at room temperature, repeat withsolvent heated to 90-95° C.

2) Application of Heat—Melting Temperature (Prepare Each Sample inDuplicate)

Method: Place the crushed contents of a dosage unit on a watch glass andheat using a hot plate, preferably with temperature readout, untilmelted. Determine the temperature of melting and test whether the mixbecomes sufficiently fluid to be drawn up into a Luer-lok syringe via an18, 20, 26 and 28-gauge needle. If the mix cannot be drawn into thesyringe there is no requirement to progress to a narrower needle gauge.Pre-weigh the syringe and then draw the syringe plunger back, maintainmaximum pressure for 30 seconds or until the syringe has equilibratedpressure to the 5 mL mark. By weighing, measure the percentage enteringinto the syringe.

3) Syringeability After Preparation in Water and Multi-Pass Filtering(Prepare Each Sample in Triplicate)

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of water at ambient temperaturefor up to 30 minutes or until the solution is homogenous. Test whetherthe mix becomes sufficiently fluid to be drawn up into a Luer-loksyringe via an 18-gauge needle (or as otherwise agreed upon withAlcobra, based on previous studies). Place a cigarette filter in themortar and allow it to absorb the liquid. Place the needle in thecigarette filter, draw back the syringe plunger to the 5 mL mark,maintaining a maximum pressure for 30 seconds or until the syringe hasequilibrated pressure. If approximately 1 mL or greater has been drawninto the syringe and is fluid enough to be expelled through the needle(for injection) then remove from the cigarette filter and dispense thesyringe contents into a suitably sized vessel. Repeat the filteringprocess twice more or until the fluid is translucent. Where thisproduces a translucent solution, dispense into a suitably sizedvolumetric flask and dilute with Assay diluent to an appropriateconcentration. Quantify the amount of API available for injection (byHPLC). If a translucent solution is not achieved after three filtrationsteps, stop and do not analyze the solution.

8. Target Assessment Criteria

Test Description Target Criteria Physical % API recovery from the 500 μm<10% Manipulation sieve (coffee grinder and with Flux) Chemical APIquantity extracted (timepoint, For Information, Extraction solvent,volume, temperature) <Comparator Syringeability API quantity (weight andvolume) <5% syringeable (solvent,, temperature, needle gauge, filter)

Supplement I Method Conditions

Weights and volumes are given for guidance only and may be modifiedprovided the final working concentration and the ratios of componentsremain the same.

Note: Additional filtration steps, dilutions and guard columns may berequired to prevent damage to HPLC systems and to produce results withinthe validated range of the method.

1 Reagents

Trifluoroacetic acid HPLC Grade (≥99.0%) or equivalent Water HPLC Gradeor equivalent Acetonitrile HPLC Grade or equivalent Ammonium HydroxideAnalytical Reagent Grade or equivalent

2 Safety

Dextroamphetamine sulfate Refer to COSHH A010 Acetonitrile Refer toCOSHH R008 Trifluoroacetic acid Refer to COSHH R041 Ammonia Refer toCOSHH R070

3 Chromatographic Conditions

Column Phenomenex Prodigy C18, 150 × 3.0 mm, (5 μm) Guard Column C18guard column as required Flow rate 0.7 mL/min Injection volume 20 μLColumn temperature 40 ° C. Detection Wavelength 257 nm Mobile phase ATFA: Water: Acetonitrile 90/0.5/10 v/v/v (pH 2.2) Mobile phase B 100%Acetonitrile Gradient Time (min) % A % B 0 100 0 15 65 35 20 0 100 22 0100 23 100 0 30 100 0 Run time 30 min

Expected Rt (Dextroamphetamine sulfate)—Approximately 6-7 min

4 Preparation of Mobile Phase A/Diluent

-   -   Dissolve 5 mL of Trifluoroacetic Acid in 900 mL of water.    -   Adjust to a pH of 2.2(±0.1) with Ammonium Hydroxide.    -   Add 100 mL of Acetonitrile and mix.    -   Allow to equilibrate to room temperature before use.

5 Preparation of Mobile Phase B

Transfer 1000 mL of HPLC grade Acetonitrile into an appropriatecontainer.

6 Preparation of Reference Standards (Prepare in Duplicate)

-   -   Accurately weigh approximately 25 mg of Dextroamphetamine        sulfate reference standard into a 100 mL volumetric flask.    -   Add approximately 80 mL of diluent and sonicate until the drug        substance is fully dissolved.    -   Dilute to volume with diluent and mix well. This is the        Dextroamphetamine sulfate standard solution (0.25 μg/mL).

7 Preparation of Sample Solutions (Prepare in Duplicate)

10 mg Dose

-   -   Place 5 capsules in a 200 ml volumetric flask.    -   dd approximately 160 mL of diluent and shake for 2 hours at 37°        C.    -   Allow to cool and dilute to volume with diluent.    -   Filter and aliquot using 0.45 μm Nylon or GHP filter and analyze        using the conditions specified in Section 3.

8 Procedure

Allow mobile phase to flow through the system until equilibrated and aconsistent baseline is achieved.

8.1 System Precision

Calculate the % relative standard deviation (% RSD) of theDextroamphetamine sulfate peak area for six injections ofDextroamphetamine sulfate Standard 1. The % RSD must not be more than2.0%.

Calculate the % relative standard deviation (% RSD) of theDextroamphetamine sulfate peak area for each of the bracketing standardsthroughout the run. The % RSD must not be more than 2.0%.

System Verification

Verify the response factors of the Dextroamphetamine sulfate peak areafor two injections of Standard 2 relative to the last two injections ofStandard 1. Standard 2 must verify as 98.0-102.0% of Standard 1.

No peaks should be detected in either of the diluent blanks which mayinterfere with the Dextroamphetamine sulfate and have an area which isgreater than 0.5% of that observed for Standard 1.

9 Typical Sequence

Blank (x2) Confirm absence of interference Std 1 (x6) Calculate systemprecision, standard verification Std 2 (x2) Standardverification/Bracketing standard, Sample 1 (x1) Single sample solution,single injection Sample 2 (x1) Single sample solution, single injectionSample 3 (x1) Single sample solution, single injection Sample 4 (x1)Single sample solution, single injection Std 2 (x1) Bracket up to 4sample injection with single standard set etc.

10 Calculations

${{Assay}\mspace{14mu}\left( {\%\mspace{14mu}{LC}} \right)} = {\frac{R\mspace{14mu}{sample}}{R\mspace{14mu}{standard}} \times \frac{W\mspace{14mu}{std}}{{Standard}\mspace{14mu}{DF}} \times \frac{{Sample}\mspace{14mu}{Df}}{N \times {Dose}} \times {Pstd} \times 1000}$

Where:

-   -   R sample Area response of the Dextroamphetamine sulfate in the        sample chromatogram (mAU*s)    -   R standard Mean area response of the Dextroamphetamine sulfate        bracketing standards (mAU*s)    -   W std Bracketing standard weight (mg)    -   P std Purity of the standard (%)    -   Sample DF Volume of sample flask (mL)    -   Standard Volume of standard flask (mL)    -   DF    -   N The number of capsules used in the sample preparation

Supplement II

TABLE I Solvent boiling points and extraction temperatures. (Refer roRisk Assessment RA058) Proposed Extraction Boiling Temperature COSHHCOSHH Solvent Point (° C.) (° C.) Reference* Category* Acetone 56   50R218 III Methanol 64.7 50 R035 III Mineral (White) Spirit  65** 50 R172III 95% Ethanol 78   60 R095 I IPA 82   60 R092 III Water/Carbonatedsoft 100   90 R143 I drink 0.1 N HC1 100   90 R031 III 0.1 N NaOH 100  90 R061 II 0.2% Sodium Bicarbonate 100   90 R147 I 8% Acetic Acid 118  90 R032 I *As SOP-EHS-0563 **conservative estimate due to low flashpoint

Supplement III

TABLE I Needle Gauges and Internal diameters Needle Gauge InternalDiameter* 18 0.84 20 0.60 23 0.34 26 0.26 28 0.18 * As Sigma UK NeedleGauge chart. Precise IDs may vary by manufacturer.

APPENDIX B Protocol Addendum for the Evaluation of Abuse DeterrentImmediate Release Formulations of Dextroamphetamine Sulfate

1. Introduction

This protocol addendum is intended to capture several tests in additionto those identified in the original protocol The outcomes from thisevaluation and those in the original protocol together should enable theselection of a better-characterized lead prototype to be furtherdeveloped into a final ADF-IR-d-amph.

2. Objectives

To evaluate the relative susceptibility to manipulation/abuse of novelprototypes of IR d-amph 10 mg liquid fill capsules (which utilize theAbusolve™ technology) as compared to a related reference product (asappropriate).

It should be noted that there is no specific relevant regulatoryguidance issued by the FDA for non-opiate drugs and therefore the testsincluded in this protocol addendum are adopted from the FDA guidance forOpioids with the appropriate adaptations (ref: FDA Guidance:Abuse-Deterrent Opioids—Evaluation and Labelling, April 2015). Referenceis also made to the March 2016 FDA guidance “General Principles forEvaluating the Abuse Deterrence of Generic Solid Oral Opioid DrugProducts” from which appropriate elements and approaches were alsoadopted.

3. Materials

All materials used should be recorded in the laboratory notebook andreported along with the results in the final report. Informationrecorded should include material name, supplier, source, batch number,expiry date and received raw material number, where appropriate.

4. Equipment

-   -   Grade A, Laboratory Glassware.    -   5/6 place analytical balance.    -   Ultrasonic and shaking water baths.    -   Sieves (various sizes) and Sieve shaker.    -   Fume hood.    -   Mortars and pestles.    -   Luer-lok syringe (no black or rubber septum syringes to be        used).    -   18 to 26 gauge syringe needles.    -   Various filters.

Analytical equipment must be qualified, calibrated and maintained inaccordance with site procedures, prior to use. Details of the equipmentused (including make and model) will be recorded in laboratory notebooksor worksheets as appropriate. Where needed additional equipment may beused and will be recorded appropriately.

5. Record Keeping

All analytical work will be recorded in project specific laboratorynotebooks. A report which will include full details of all results andsubsequent evaluations against any acceptance criteria will betranscription and calculation checked prior to issue. In addition,wherever possible and in all testing that include manipulation of thedosage form (such as syringeability), video recording and still imageswill be taken and attached to the report.

6. Analytical Methods

Some evaluations are based on visual/physical assessments; othersrequire analysis of the amount of drug substance. The analytical methodsused are based on compendial methods for Dextroamphetamine which havebeen verified for selectivity and may require limited further validationat a later stage of development. Where indicated, the method will beused (and modified as necessary) to determine either a % assay or a %release profile for Dextroamphetamine sulfate when applicable.

Dextroamphetamine sulfate extraction will be determined by the HPLCmethod detailed in Supplement I for the IR-ADF prototype products.

7. Evaluation Plan

The physical/chemical deterrent methods in this protocol will beevaluated on the following prototype formulations:

mg/capsule Component Prototype 2 Dextroamphetamine sulfate 10  Poloxamer 124 70   Gelucire 48/16 52.5 Kelcogel GCHA 52.5 Kolliphor EL —CMC 7H3SF Capsule Shell and Size Size 3 gelatin Total fill weight (mg)*185   *Final fill weight to be confirmed experimentally

Barr's 10 mg Dextroamphetamine sulphate Tablets will also be evaluatedas a comparator under the same test strategy (where applicable).

Physical and Chemical Abuse Resistance Testing

All testing will employ whole dose units of Prototype 2. Physicaltesting will be conducted in duplicate, and all other testing intriplicate. Where physical testing produces poor replicates, a thirdtest should be performed.

7.1 Test of Syringeability

For Prototype 2 Formulation and Comparator Only

Syringeability in different gauge needles after preparation with ambientand heated water (Prepare each sample in triplicate)

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 5 mL of water at ambient temperaturefor up to 30 minutes or until the solution is homogenous. Test whetherthe mix becomes sufficiently fluid to be drawn up into a Luer-loksyringe via a 26-gauge needle. Draw back the syringe plunger to the 5 mLmark, maintaining a maximum pressure for 30 seconds or until the syringehas equilibrated pressure. If approximately 1 mL or greater has beendrawn into the syringe and is fluid enough to be expelled through theneedle (for injection) then dispense the syringe contents into asuitably sized volumetric flask and dilute with Assay diluent to anappropriate concentration. Quantify the amount of API available forinjection by HPLC.

Repeat section 7.1 using water heated to 90-95° C.

Repeat the above experiment for ambient and heated water using narrowergauge needles (18, 20 and 23 gauge).

7.2 Test Abuse Involving Chemical Extraction

For prototype 2 formulation and comparator only

1) Extraction in Small Volumes of Ambient 0.2% Sodium BicarbonateSolution (Prepare each Sample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 5 mL of 0.2% Sodium Bicarbonatesolution solvent for 5 minutes or until homogeneous. Transfer theresulting suspension to a suitable scintillation vial, cover the lid inparafilm and shake in a water bath at ambient temperature, sampling at60 minutes. Filter the sample through a 0.45 μm filter into a flask anddilute to an appropriate concentration with the standard assay methoddiluent. Quantify the API concentration by HPLC, analysing

An intermediate filtration step over Whatman filter paper (e.g. Grade 4)may be used where 0.45 μm filters become blocked. In this instance, openfunnels and vessels should be covered in parafilm during filtration tominimise evaporation and an evaporation standard, prepared as method butfiltered over Whatman should be prepared in addition to or from aportion of the assay standard.

Repeat the experiment using 2 ml of ambient 0.2% Sodium Bicarbonatesolution

2) Extraction in Small Volumes of Hot 0.2% Sodium Bicarbonate Solution(Prepare Each Sample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 5 mL of pre-heated 0.2% SodiumBicarbonate solution for 5 minutes or until homogeneous. Transfer theresulting suspension to a suitable scintillation vial, cover the lid inparafilm and shake in a water bath at the temperature indicated inSupplement II: Table I, taking samples at 60 minutes. Filter the samplethrough a 0.45 μm filter into a flask and dilute to an appropriateconcentration with the standard assay method diluent. Quantify the APIconcentration by HPLC,

As previously, an intermediate filtration step over Whatman filter paper(e.g. Grade 4) may be used where 0.45 μm filters become blocked.

Repeat the experiment using 2 ml of heated 0.2% Sodium Bicarbonatesolution 7.3 Ethanol extraction test

7.3 For Prototype 2 Formulation Only

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of 95% Ethanol solution for 5minutes or until homogeneous. Filter the sample through a 0.45 μm nylonfilter into a round bottom flask. Evaporate the Ethanol off by addingthe round bottom flask containing the solution to a beaker full of wateron a hot plate.

Observe, document and photograph the resultant mixture.

If the resultant mixture exhibits a powder-like consistency then subjectit to the insufflation assessment.

APPENDIX C Protocol Addendum for the Evaluation of Abuse DeterrentImmediate Release Formulations of Dextroamphetamine Sulfate

1. Introduction

Alcobra has engaged Encap Drug Delivery (Encap) to provide developmentservices for a novel abuse deterrent formulation (ADF) ofdextroamphetamine sulfate (d-amph), targeting a comparable dissolutionprofile to Barr's 10 mg Dextroamphetamine approved Immediate Release(IR) tablet product. Based on preliminary development efforts andinitial evaluations, 3 prototype formulations have been identified asthe most promising leads to be further evaluated more extensively forabuse deterrence properties. This protocol addendum is intended tocapture several tests in addition to those identified in the originalprotocol The outcomes from this evaluation and those in the originalprotocol together should enable the selection of a better-characterizedlead prototype to be further developed into a final ADF-IR-d-amph.

2. Objectives

To evaluate the relative susceptibility to manipulation/abuse of novelprototypes of IR d-amph 10 mg liquid fill capsules (which utilize theAbusolve™ technology) as compared to a related reference product (asappropriate).

It should be noted that there is no specific relevant regulatoryguidance issued by the FDA for non-opiate drugs and therefore the testsincluded in this protocol addendum are adopted from the FDA guidance forOpioids with the appropriate adaptations (ref: FDA Guidance:Abuse-Deterrent Opioids—Evaluation and Labelling, April 2015). Referenceis also made to the March 2016 FDA guidance “General Principles forEvaluating the Abuse Deterrence of Generic Solid Oral Opioid DrugProducts” from which appropriate elements and approaches were alsoadopted.

3. Materials

All materials used should be recorded in the laboratory notebook andreported along with the results in the final report. Informationrecorded should include material name, supplier, source, batch number,expiry date and received raw material number, where appropriate.

4. Equipment

-   -   Grade A, Laboratory Glassware.    -   5/6 place analytical balance.    -   Ultrasonic and shaking water baths.    -   Sieves (various sizes) and Sieve shaker.    -   Fume hood.    -   Mortars and pestles.    -   Luer-lok syringe (no black or rubber septum syringes to be        used).    -   18 to 26 gauge syringe needles.    -   Various filters.    -   Domestic grater.    -   Microwave    -   Oven

Analytical equipment must be qualified, calibrated and maintained inaccordance with site procedures, prior to use. Details of the equipmentused (including make and model) will be recorded in laboratory notebooksor worksheets as appropriate. Where needed additional equipment may beused and will be recorded appropriately.

5. Record Keeping

All analytical work will be recorded in project specific laboratorynotebooks. A report which will include full details of all results andsubsequent evaluations against any acceptance criteria will betranscription and calculation checked prior to issue. In addition,wherever possible and in all testing that include manipulation of thedosage form (such as syringeability), video recording and still imageswill be taken and attached to the report.

6. Analytical Methods

Some evaluations are based on visual/physical assessments; othersrequire analysis of the amount of drug substance. The analytical methodsused are based on compendial methods for Dextroamphetamine which havebeen verified for selectivity and may require limited further validationat a later stage of development. Where indicated, the method will beused (and modified as necessary) to determine either a % assay or a %release profile for Dextroamphetamine sulfate when applicable.

Dextroamphetamine sulfate extraction will be determined by the HPLCmethod detailed in Supplement I for the IR-ADF prototype products.

7. Evaluation Plan

The physical/chemical deterrent methods in this protocol will beevaluated on the following prototype formulations:

mg/capsule Component Prototype 2 Dextroamphetamine sulfate 10  Poloxamer 124 70   Gelucire 48/16 52.5 Kelcogel GCHA 52.5 Capsule Shelland Size Size 3 gelatin Total fill weight (mg)* 185   *Final fill weightto be confirmed experimentally

-   -   Barr's 10 mg Dextroamphetamine sulphate Tablets will also be        evaluated as a comparator under the same test strategy (where        applicable).

Physical and Chemical Abuse Resistance Testing

All testing will employ whole dose units of Prototype 2. Physicaltesting will be conducted in duplicate, and all other testing intriplicate. Where physical testing produces poor replicates, a thirdtest should be performed.

7.1 Tests of Physical Barriers to Abuse by Crushing, Cutting or Grinding

Each test in this section should include five (5) whole dose units.Prototype 2 as well as the comparator compound should be tested. Recordany observations such as the inability to grind the material or pass itthrough the sieve due to a waxy or other physical characteristic.Video/picture documentation should be included wherever possible.

1) Effects of Heating Pre Treatment

Method: Pre-treat the dosage units in an oven set at 105° C. for 24 hrs.Remove the shells as quickly as possible with a scalpel then immediatelyafter the shell is removed, grind with a coffee grinder for one minute.Observse capsules after one minute grinding and if it appears that theparticle size can be further reduced continue grinding in the coffeegrinder for up to 5 minutes in total and note exact time in thelaboratory notebook.

Determine the particle size distribution of the 5 capsule contents bypouring them onto the following sieve assembly: 1000, 500, 250, and 106microns. Attempts can be made to further reduce any large particles bysqueezing them with your fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

Repeat above experiment pre-treating the dosage units in a microwave atfull power (700-800 W) for 4 minutes (if time capsules are in themicrowave requires to be longer or shorter than 4 minutes this will bedocumented in the laboratory note book).

2) Effects of Using Different Household Tools

Method: Freeze the dosage units in a domestic freezer for 24 hrs. Removethe shells as quickly as possible with a scalpel then immediately afterthe shell is removed, grate the capsule contents with a small domesticgrater. Determine the particle size distribution of the 5 capsulecontents by pouring them onto the following sieve assembly: 1000, 500,250, and 106 microns. Attempts can be made to further reduce any largeparticles by squeezing them with your fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

Repeat the above experiment using a scalpel blade to finely cut thecapsule contents.

3) Milling with a Coffee Grinder (Extended Grinding Time)

Method: Freeze the dosage units in a domestic freezer for 24 hrs. Removethe shells as quickly as possible with a scalpel then immediately afterthe shell is removed, grind with a coffee grinder for five minutes.Determine the particle size distribution of the 5 capsule contents bypouring them onto the following sieve assembly: 1000, 500, 250, and 106microns. Attempts can be made to further reduce any large particles bysqueezing them with your fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

4) Effects of Cooling with Dry Ice

Method: Freeze the dosage units using dry ice for 10 minutes. Carefullyremove the shells as quickly as possible with a scalpel then immediatelyafter the shell is removed, grind with a coffee grinder for one minutesincorporating sufficient pellets of dry ice to keep the contents cold.Determine the particle size distribution of the 5 capsule contents bypouring them onto the following sieve assembly: 1000, 500, 250, and 106microns. Attempts can be made to further reduce any large particles bysqueezing them with your fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

5) Effects of Cooling Grinder

Method: Place the section of the grinder the capsules are placed in afreezer for an hour. Freeze the dosage units in a domestic freezer for24 hrs. Carefully remove the shells as quickly as possible with ascalpel then immediately after the shell is removed, grind with a coffeegrinder for one minutes. Determine the particle size distribution of the5 capsule contents by pouring them onto the following sieve assembly:1000, 500, 250, and 106 microns. Attempts can be made to further reduceany large particles by squeezing them with your fingers.

Mechanically shake the sieve assembly for 5 minutes and determine ifanything passes through. Weigh any material that has passed through eachsieve.

Determine API/Excipient segregation as required: Assay the material oneach sieve. Calculate the approximate total capsule weight and % APIrecovery if sufficient material has passed through to facilitate ananalysis.

7.2 Test of Syringeability

For Prototype 2 Formulation and Comparator Only

1) Syringeability in Different Gauge Needles after Preparation withWater (Prepare Each Sample in Triplicate)

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of a dose unit, then grind with 10 mL of water at ambienttemperature for 5 minutes or until the solution is homogenous. Testwhether the mix becomes sufficiently fluid to be drawn up into aLuer-lok syringe via an 18-gauge needle. Draw back the syringe plungerto the 10 mL mark, maintaining a maximum pressure until all solutionwhich is syringeable has been drawn in to the syringe. If a quantifiableamount has been drawn into the syringe and is fluid enough to beexpelled through the needle (for injection) then dispense the syringecontents into a suitably sized volumetric flask and dilute with Assaydiluent to an appropriate concentration. Quantify the amount of APIavailable for injection by HPLC.

Repeat the above, attempting to draw the fluid via a cigarette filtertip. A fresh sample should be prepared for each filter used.

Repeat the above experiment using a narrower gauge needle for anysamples that were syringeable with the 18-gauge needle and progress viathe 20, 23 and 26 gauge needles as long as the recovered quantity of APIis greater than 5%.

Repeat syringeability with water heated to 90-95° C.

2) Syringeability in Water using Multiple Capsules

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of 3 dose units, then grind with 10 mL of water at ambienttemperature for 5 minutes or until the solution is homogenous. Testwhether the mix becomes sufficiently fluid to be drawn up into aLuer-lok syringe via an 18-gauge needle. Draw back the syringe plungerto the 10 mL mark, maintaining a maximum pressure until all solutionwhich is syringeable has been drawn in to the syringe. If a quantifiableamount has been drawn into the syringe and is fluid enough to beexpelled through the needle (for injection) then dispense the syringecontents into a suitably sized volumetric flask and dilute with Assaydiluent to an appropriate concentration. Quantify the amount of APIavailable for injection by HPLC.

Repeat the experiment with water heated to 90-95° C.

3) Syringeability in Water After Extensive Grinding of Dosage Units

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of 1 dose unit, then grind with 10 mL of water at ambienttemperature for 30 minutes, photographing the mixture after every 5minutes of grinding. Test whether the mix becomes sufficiently fluid tobe drawn up into a Luer-lok syringe via an 26-gauge needle. Draw backthe syringe plunger to the 10 mL mark, maintaining a maximum pressureuntil all solution which is syringeable has been drawn in to thesyringe. If a quantifiable amount has been drawn into the syringe and isfluid enough to be expelled through the needle (for injection) thendispense the syringe contents into a suitably sized volumetric flask anddilute with Assay diluent to an appropriate concentration. Quantify theamount of API available for injection by HPLC.

7.3 Test Abuse Involving Chemical Extraction

For Prototype 2 Formulation and Comparator Only

1) Extraction in Small Volumes of Ambient, Ethanol 40% and Ethanol 95%(Prepare Each Sample in Triplicate).

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 5 mL of 40% Ethanol for 5 minutes oruntil homogeneous. Transfer the resulting suspension to a suitablescintillation vial, cover the lid in parafilm and shake in a water bathat ambient temperature, sampling at 60 minutes. Filter the samplethrough a 0.45 μm filter into a flask and dilute to an appropriateconcentration with the standard assay method diluent. Quantify the APIconcentration by HPLC, analysing

An intermediate filtration step over Whatman filter paper (e.g. Grade 4)may be used where 0.45 μm filters become blocked. In this instance, openfunnels and vessels should be covered in parafilm during filtration tominimise evaporation and an evaporation standard, prepared as method butfiltered over Whatman should be prepared in addition to or from aportion of the assay standard.

Repeat the above experiment with 95% Ethanol.

7.4 Turpentine and/or 0.2% Sodium Bicarbonate Extraction Test

For Prototype 2 Formulation and the Comparator Only

Method: Crush with a mortar and pestle or otherwise reduce the particlesize of the dose, then grind with 10 mL of turpentine solution for 5minutes or until homogeneous. Filter the sample through a 0.45 μm nylonfilter into a round bottom flask. Evaporate the turpentine off by addingthe round bottom flask containing the solution to a beaker full of wateron a hot plate.

Observe, document and photograph the resultant mixture.

If the resultant mixture exhibits a powder-like consistency then subjectit to the insufflation assessment.

Repeat the experiment extracting dosage units in 0.2% sodium bicarbonatesolution.

APPENDIX D Protocol Addendum for the Evaluation of Smokeability of anAbuse Deterrent Immediate Release Formulations of DextroamphetamineSulfate

1. Introduction

This protocol is designed to evaluate prototype 2 physical barriers toabuse by smoking. The outcomes from this evaluation should enable theselection of a better-characterized lead prototype to be furtherdeveloped into a final ADF-IR-d-amph.

2. Objectives

To evaluate the relative susceptibility to manipulation/abuse by smokingof novel prototypes of IR d-amph 10 mg liquid fill capsules as comparedto a related reference product (as appropriate).

It should be noted that there is no specific relevant regulatoryguidance issued by the FDA for non-opiate drugs and therefore the testsincluded in this protocol are adopted from the FDA guidance for Opioidswith the appropriate adaptations (ref: FDA Guidance: Abuse-DeterrentOpioids—Evaluation and Labelling, April 2015). Reference is also made tothe March 2016 FDA guidance “General Principles for Evaluating the AbuseDeterrence of Generic Solid Oral Opioid Drug Products” from whichappropriate elements and approaches were also adopted.

3. Materials

All materials used should be recorded in the laboratory notebook andreported along with the results in the final report. Informationrecorded should include material name, supplier, source, batch number,expiry date and received raw material number, where appropriate.

4. Equipment

-   -   Grade A, Laboratory Glassware.    -   5/6 place analytical balance.    -   Fume hood.    -   Various filters.    -   Sand bath    -   Heating Mantle    -   Calibrated thermometer    -   Cooling device

Analytical equipment must be qualified, calibrated and maintained inaccordance with site procedures, prior to use. Details of the equipmentused (including make and model) will be recorded in laboratory notebooksor worksheets as appropriate. Where needed additional equipment may beused and will be recorded appropriately.

5. Record Keeping

All analytical work will be recorded in project specific laboratorynotebooks. A report which will include full details of all results andsubsequent evaluations against acceptance criteria will be transcriptionand calculation checked prior to issue. In addition, wherever possibleand in all testing that include manipulation of the dosage form, videorecording and still images will be taken and attached to the report.

6. Analytical Methods

Some evaluations are based on visual/physical assessments; othersrequire analysis of the amount of drug substance. The analytical methodsused are based on compendial methods for Dextroamphetamine which havebeen verified for selectivity and may require limited further validationat a later stage of development. Where indicated, the method will beused (and modified as necessary) to determine a % assay forDextroamphetamine sulfate when applicable.

Dextroamphetamine sulfate extraction will be determined by the HPLCmethod detailed in Supplement I for the IR-ADF prototype and using thecurrent USP tablet method for the comparator, Barr's Dextroamphetaminesulfate 10 mg.

7. Evaluation Plan

The physical/chemical deterrent methods in this protocol will beevaluated on the following prototype formulation:

mg/capsule Component Prototype 2 Dextroamphetamine sulfate 10  Poloxamer 124 70   Gelucire 48/16 52.5 Kelcogel GCHA 52.5 Capsule Shelland Size Size 3 gelatin Total fill weight (mg)* 185   *Final fill weightto be confirmed experimentally

Barr's 10 mg Dextroamphetamine Sulfate tablets will also be evaluated asa comparator under the same test strategy.

Physical Abuse Resistance Testing

All testing will employ three (3) whole dose units. Testing will beconducted in duplicate. Where testing produces poor replicates, a thirdtest should be performed.

7.1 Test of Smokability Barriers (To Determine if DextroamphetamineTablet and Capsules Formulations can be Abused by Smoking)

The process of “smoking” a drug involves application of a heat sourcethat is sufficient to vapourise by sublimation a portion of the drug ina localised manner such that the resulting vapour can be inhaled. Thereis no recognised method of testing this route of abuse therefore, inorder to assess the feasibility of it in the laboratory, the followingexperiment has been designed to capture any potentially volatilised APIin an enclosed vessel.

The contents of the collection vessel and the original heated vessel canbe assayed to quantify amounts of API present and also to determine ifthe API has decomposed (degraded). A temperature of 233° C. has beenselected since this is the ignition temperature of paper.

For the test, use three whole dose units of both the comparator productand formulation prototype 2. Record any observations noted throughouteach test. Video/picture documentation will be included whereverpossible.

Smokability barriers (prepare in duplicate):

Prototype 2:

Open three full dose units of prototype 2 with a scalpel and add to a 50ml round bottom flask. Place the flask in a sand bath connected to theapparatus shown in FIG. 1 .

Comparator:

Add three full dose units of the comparator to a 50 ml round bottomflask. Place the flask in a sand bath connected to the apparatus shownin FIG. 1 .

For both Prototype 2 and the Comparator:

Heat the sand bath to 233° C. and hold for 15 minutes. Observe thedosage units over those 15 minutes and photograph or video whenpossible.

Prototype 2:

Add 30 ml of diluent to the original flask containing the capsules andmix thoroughly. Sonicate if required to aid dissolution of the sample.Filter an aliquot of this solution through a 0.45 μm nylon filter,discarding the first 2 ml to waste then pipette 1 ml of the resultantfiltrate into a 10 ml volumetric flask and dilute to volume withdiluent.

Inspect the 25 ml round bottom collection flask for evidence of anysublimed API which has vapourised and and condensed. If any residue isapparent then add an appropriate amount of assay diluent to the flask(eg 2-5 ml) and mix thoroughly.

Comparator:

Add 30 ml of diluent to the original flask containing the comparatortablets and mix thoroughly. Sonicate if required to aid dissolution ofthe sample. Filter an aliquot of this solution through a 0.45 μm nylonfilter, discarding the first 2 ml to waste then pipette 2 ml of theresultant filtrate into a 10 ml volumetric flask and dilute to volumewith diluent.

Inspect the 25 ml round bottom collection flask for evidence of anysublimed API which has vapourised and and condensed. If any residue isapparent then add an appropriate amount of assay diluent to the flask(eg 2-5 ml) and mix thoroughly.

Assay each solution by HPLC analysis in order to quantify thedextroamphetamine present.

Encap Analytical Method

2.3. Dissolution Conditions

2.3.1 Dissolution Apparatus

Dissolution Apparatus USP apparatus III Filter Type 40/35 μm probefilter Medium Type 0.01 M HCl Medium Volume 250 ml Sample Times 5, 10,15, 20, 30 and 45 minutes Sample Volume 2 ml (filter not replaced)Vessel Temperature 37° C. ± 0.5° C. Dip Rate 30 dips per minute MeshScreen Size 840 micron

2.3.2 HPLC Conditions

Column Gemini C18 5 μm 110A 150 mm × 4.6 mm Flow Rate 1.5 ml/minInjection volume 20 μ1 Column temperature 50° C. Detection wavelength210 nm Mobile phase 100% mobile phase as section 2.4.2 Run Time 10 minExpected Rt 4.6 min

2.4 Preparation of Reagents

Weights and volumes are given for guidance only and may be modifiedprovided the final working concentration and the ratios of componentsremains the same.

2.4.1 Dissolution Medium: 0.01M HCl

0.1M HCl prepared by dissolving 8.5 ml of Hydrochloric acid in 800 mlUHQ water, mixed well then made to volume in a 1000 ml Volumetric flask.

To prepare 1 litre of 0.01M HCl, 100 ml of 0.1M HCl dissolved in 900 mlof UHQ Water and mixed well.

2.4.2 Preparation of Mobile Phase

To prepare 1 litre of mobile phase:

-   -   Dissolve 1.1 g of Sodium-l-heptanesulfonate in 575 ml of UHQ        water.    -   Add 25 ml of dilute glacial acetic acid (14 ml acetic acid into        100 ml UHQ water).    -   Add 400 ml of Methanol.    -   Measure the pH of this solution. A pH of 3.3±0.1 is acceptable.        If required, adjust the pH accordingly using dropwise addition        of glacial acetic acid.

2.5 Preparation of Standard Solution (Prepare in Duplicate)

Note: Weights and volumes are included for guidance only and may bemodified provided the final working concentration remains the same.

Accurately weigh 8 mg of Dextroamphetamine Sulfate into a 200 mlvolumetric flask. Add 150 ml of dissolution media and sonicate for 10minutes to dissolve. Once cooled, dilute to volume with dissolutionmedia. This is the working standard solution for DextroamphetamineSulfate.

-   -   Reference standard solutions are stable for 4 days at ambient or        refrigerated conditions in clear glassware.

2.6 Dissolution Procedure

Weigh each capsule before analysis for information only.

Decant 250 ml of dissolution medium into each vessel and equilibrate to37° C.±0.5° C. Place one capsule in the sample inner tube prior toattaching to the sample holder and lowering into the vessel.

Remove 2 ml at each time point: 5, 10, 15, 20, 30 and 45 minutes with acannula attached with a 40/35 μm probe filter.

Transfer filtered sampled solution into a HPLC vial for analysis.

2.7 HPLC Procedure

Allow mobile phase to flow through the system until equilibrated and aconsistent baseline is achieved.

2.7.1 System Precision

Calculate the relative standard deviation (RSD) of the meanDextroamphetamine Sulfate peak area for six injections of standard 1.The RSD is not more than 2%.

2.7.1 Standard Verification

Verify the mean peak response factors of two injection of standard 2relative to the response factor of the last two injection of Standard 1.Standard 2 must verify as 98-102% of standard 1.

2.7.3 Repeatability Throughout the Run

Calculate the relative standard deviation (% RSD) of the peak area forall of the bracketing standards throughout the run. The RSD is not morethan 2%.

2.7.4 Specificity

There must be no interference greater than or equal to 1.0% of the meanreference standard peak area in the blank injections at the retentiontime of the peak.

2.7.5 Typical Injection

Sequence Blank (x2) Confirm absence of interference Standard 1 (x6)Calculate system precision Standard 2 (x1) Calculate standardverification Sample 1a (x1) Single sample solution, single injectionSample 1b (x1) Single sample solution, single injection Sample 1c (x1)Single sample solution, single injection Sample 1d (x1) Single samplesolution, single injection Sample 1e (x1) Single sample solution, singleinjection Sample 1f (x1) Single sample solution, single injectionStandard 2 (x1) Bracket six samples between each standard Sample 2a (x1)Single sample solution, single injection Sample 2b (x1) Single samplesolution, single injection Sample 2c (x1) Single sample solution, singleinjection Sample 2d (x1) Single sample solution, single injection Sample2e (x1) Single sample solution, single injection Sample 2f (x1) Singlesample solution, single injection Standard 2 (x1) Bracket six samplesbetween each standard Sample 3a (x1) Single sample solution, singleinjection etc.

2.8 Calculations

Determine the % release for each product relative to the referencestandard material using the equation.

% Release

$\left( {\%\mspace{14mu}{Release}} \right) = {\begin{matrix}{Asam} \\{Astd}\end{matrix} \times \begin{matrix}{Wstd} \\{Dose}\end{matrix} \times \begin{matrix}{Volsmp} \\{Volstd}\end{matrix} \times {Pstd} \times 100}$

Where:

-   -   Asam Area response for Dextroaphetamine Sulfate in the sample        chromatogram    -   Astd Mean area response of bracketing standard injections    -   Wstd Bracketing standard weight (mg)    -   Pstd Purity of the standard (decimal form or mg/mg)    -   Vol smp Volume of dissolution medium at the time point (ml)    -   Vol std Dilution factor of reference standard (ml)    -   Dose Theoretical content of Dextroaphetamine Sulfate in a single        capsule (mg)

Correct for volume of media removed at each dissolution time-point.Report the % Release to 1 decimal place for individual pots.

3. Revision History

3.1 New June 2016

Encap Analytical Method EAM0297 vs. 01

APPENDIX E

1. Purpose

This method will be used in the Dissolution testing and analysis ofDextroamphetamine Sulfate in 10 mg capsules. This is an HPLC methodusing a reverse phase C18 column and UV detection at 210 nm.

2. Method Conditions

2.1. Reagents

Sodium-1-HeptaneSulfonate Analytical Grade or equivalent Water HPLCgrade or equivalent Acetic Acid Glacial HPLC grade or equivalentMethanol HPLC grade or equivalent Hydrochloric Acid Analytical Grade orequivalent Dextroamphetamine Sulfate USP Reference Standard

2.2. Safety

Sodium-l-HeptaneSulfonate Refer to COSHH assessment R027 Water Refer toCOSHH assessment R143 Acetic Acid Glacial Refer to COSHH assessment R032Methanol Refer to COSHH assessment R035 Hydrochloric Acid Refer to COSHHassessment R031 Dextroamphetamine Sulfate Refer to COSHH assessment A010

2.3. Method Conditions

2.3.1 Dissolution Apparatus

Dissolution apparatus USP apparatus I Filter type 35 μm probe filterMedium type 0.01 M HCl Medium volume 500 ml Sample times 5, 10, 15, 20,30 and 45 minutes. Sample volume 1.5 ml (filter not replaced) Vesseltemperature 37° C. ± 0.5° C. Speed 100 rpm

2.3.2 HPLC Conditions

Column Zorbax Eclipse XDB-C18 5 μm 250 mm × 4.6 mm Flow rate 1.5 ml/minInjection volume 100 μl Column temperature 40° C. Detection wavelength210 nm Mobile phase 100% Mobile phase Run time 20 min Expected Rt 12 min

2.4 Preparation of Reagents

Weights and volumes are given for guidance only and may be modifiedprovided the final working concentration and the ratios of componentsremains the same.

2.4.1 Dissolution Medium: 0.01M HCl

To prepare 10 litre of 0.01M HCl, add 8.5 ml of Hydrochloric acid in9000 ml of UHQ water, mix well then make to volume using UHQ water.

2.4.2 Preparation of Mobile Phase

To prepare 1 litre of mobile phase:

-   -   Dissolve 1.1 g of Sodium-1-heptanesulfonate in 575 ml of UHQ        Water.    -   Add 25 ml of dilute glacial acetic acid (14 ml acetic acid into        100 ml UHQ Water)    -   Add 400 ml of Methanol.    -   Measure the pH of this solution. A pH of 3.3±0.1 is acceptable.        If required, adjust the pH accordingly using dropwise addition        of glacial acetic acid.

2.5 Preparation of Standard Solution (Prepare in Duplicate)

Note: weights and volumes are included for guidance only and may bemodified provided the final working concentration remains the same.

-   -   Accurately weigh 6 mg of Dextroamphetamine Sulfate into a 10 ml        volumetric flask    -   Add 7 ml of dissolution media and sonicate for 10 minutes to        dissolve    -   Once cooled, dilute to volume with dissolution media. This is        the working standard solution for Dextroamphetamine Sulfate (600        μg/ml)    -   Transfer 2 ml of the stock solution into a 20 ml volumetric        flask and make to volume with dissolution media. This is the 60        μg/ml standard solution.

Reference standard solutions are stable for 4 days at ambient orrefrigerated conditions in clear glassware.

2.6 Dissolution Procedure

Weigh each capsule before analysis.

Ensure the sampling system is clean and dry and contains no residualmoisture prior to use. Fit 35 μm probe tip filters to each cannula.

Decant 500 ml of dissolution medium into each vessel and equilibrate to37° C.±0.5° C.

Place one capsule in the basket and lower into the vessel to start thedissolution testing. Set the paddle speed to 100 rpm.

Remove 1.5 ml at each time point: 5, 10, 15, 20, 30 and 45 minutes. Allsamples should be dispensed straight into labelled HPLC vials foranalysis.

2.7 HPLC Procedure

Allow mobile phase to flow through the system until equilibrated and aconsistent baseline is achieved.

2.7.1 System Precision

Calculate the relative standard deviation (RSD) of the meanDextroamphetamine Sulfate peak area for six injections of standard 1.The RSD is not more than 2%

2.7.2 Standard Verification

Verify the mean peak response factors of two injection of standard 2relative to the response factor of the last two injection of Standard 1.Standard 2 must verify as 98-102% of standard 1.

2.7.3 Repeatability Throughout the Run

Calculate the relative standard deviation (% RSD) of the peak area forall of the bracketing standards throughout the run. The RSD is not morethan 2%

2.7.4 Specificity

There must be no interference greater than or equal to 1.0% of the meanreference standard peak area in the blank injections at the retentiontime of the peak.

2.7.5 Typical Injection Sequence

Blank (x2) Confirm absence of interference Standard 1 (x6) Calculatesystem precision Standard 2 (x2) Calculate standard verification Sample1a (x1) Single sample solution, single injection Sample 1b (x1) Singlesample solution, single injection Sample 1c (x1) Single sample solution,single injection Sample 1d (x1) Single sample solution, single injectionSample 1e (x1) Single sample solution, single injection Sample 1f (x1)Single sample solution, single injection Standard 2 (x1) Bracket sixsamples between each standard etc.

2.8 Calculations

Determine the % release for each product relative to the referencestandard material using the equation.

% Release

$\left( {\%\mspace{14mu}{Release}} \right) = {\frac{A_{sam}}{A_{std}} \times \frac{W_{std}}{Dose} \times \frac{{Vol}_{smp}}{{Vol}_{std}} \times P_{std} \times 100}$

Where:

-   -   Asam Area response for Dextroamphetamine Sulfate in the sample        chromatogram    -   Astd Mean area response of bracketing standard injections    -   Wstd Bracketing standard weight (mg)    -   Pstd Purity of the standard (decimal form or mg/mg)    -   Vol smp Volume of dissolution medium at time point (ml)    -   Vol std Dilution factor of reference standard (ml)    -   Dose Theoretical content of Dextroamphetamine Sulfate in a        single capsule (mg)

Correct for volume of media removed at each dissolution time-point.Report the % Release to 1 decimal place for individual pots.

The invention claimed is:
 1. A method of deterring abuse of amedicament, comprising providing a formulation comprising themedicament, poloxamer, water-soluble anionic polysaccharide, and PEGester; wherein the medicament is

or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein the abuse is abuse by insufflation.
 3. The method of claim 1,wherein the abuse is abuse by injection.
 4. The method of claim 1,wherein the ratio of poloxamer:water-soluble anionic polysaccharide:PEGester is about 40:30:30.
 5. The method of claim 1, wherein the poloxameris poloxamer 124; wherein the water-soluble anionic polysaccharide isgellan gum; wherein the PEG ester is polyoxyl stearate; and wherein theratio of poloxamer 124:gellan gum:polyoxyl stearate is about 40:30:30.6. The method of claim 5, wherein the formulation comprises about 10 mgto about 50 mg of the medicament.
 7. The method of claim 5, wherein theformulation comprises a unit dose of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg,30 mg, 35 mg, 40 mg, 45 mg, or 50 mg of the medicament.
 8. The method ofclaim 1, wherein the poloxamer is poloxamer 124; wherein thewater-soluble anionic polysaccharide is Kelcogel CGHA; wherein the PEGester is Gelucire 48/16; and wherein the ratio of poloxamer 124:gellangum:polyoxyl stearate is about 40:30:30.
 9. A method of treatingattention-deficit/hyperactivity disorder (ADHD) in a subject byadministering to the subject an abuse-deterrent formulation comprising amedicament, poloxamer, water-soluble anionic polysaccharide, and PEGester; wherein the medicament is

or a pharmaceutically acceptable salt thereof.
 10. The method of claim9, wherein the ratio of poloxamer:water-soluble anionicpolysaccharide:PEG ester is about 40:30:30.
 11. The method of claim 9,wherein the poloxamer is poloxamer 124; wherein the water-solubleanionic polysaccharide is gellan gum; wherein the PEG ester is polyoxylstearate; and wherein the ratio of poloxamer 124:gellan gum:polyoxylstearate is about 40:30:30.
 12. The method of claim 11, wherein theformulation comprises about 10 mg to about 50 mg of the medicament. 13.The method of claim 11, wherein the formulation comprises a unit dose of5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mgof the medicament.
 14. The method of claim 9, wherein the poloxamer ispoloxamer 124; wherein the water-soluble anionic polysaccharide isKelcogel CGHA; wherein the PEG ester is Gelucire 48/16; and wherein theratio of poloxamer 124:gellan gum:polyoxyl stearate is about 40:30:30.